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https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=359297
2018 Group Project 5
2018-10-17T00:35:37Z
<p>Z5229399: /* Sjögren Syndrome */</p>
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<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
=Dorsal Root Ganglion=<br />
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==Introduction==<br />
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[[File:Dorsal Root Ganglia Adult.jpg|450px|thumb|wrap|A diagram of a cross section of an adult human spinal cord.]]<br />
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In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates that gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system that includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway that are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo{{#pmid:15590743|PMID15590743}}. <br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perception. A, B, and C nerve fibers have both different myelination sizes and soma sizes that correspond to their function in the PNS<ref name="PMID25271163"/>. The cell bodies of all of these neurons are stored in the dorsal root ganglia, and due to their pseudounipolar orientation, can send axons towards their target tissues and the spinal cord. The subpopulations of neurons can be categorized depending on whether they are responsive to nociceptive, mechanoreceptive, or proprioceptive stimuli. Through the innervation of target tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, vibrations and muscle movement<ref name="PMID27130590"/>.<br />
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<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
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==History==<br />
[[File:François Magendie.jpg|thumb|embed|100px|François Magendie]]<br />
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Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within.<br />
'''''1811 -Charles Bell''''' [[File:CharlesBell001.jpg|thumb|100px|embed|Charles Bell]]<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
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'''''1822-Francois Magendie'''''<br />
Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, Magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies, a process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
[[File:Johannes Mueller.jpg|thumb|100px|right|Johannes Peter Müller]]<br />
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'''''1830s -Johannes Peter Müller'''''<br />
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Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
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==Embryonic Origins==<br />
[[File:Embryonic dorsal root ganglia in mouse.jpg|right|300px|thumb|wrap|Antibody stain in a mouse embryo showing the location of the dorsal root ganglion]]<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Trunk Neural Crest===<br />
The induction of the neural crest is the first step of the development of DRG. NCCs undergo an epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/>.<br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/>.<br />
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===Embryonic Function===<br />
Most of the research into the embryonic development of the DRG analyzes patterning and differentiation of structures, but not embryonic functionality. One method of measuring the functionality of the DRG is through stimulation of the neurons associated with the DRG and observing reflexive responses to stimuli. By E15.5 in rat embryonic development, electrical stimulation of the dorsal root ganglion can produce a depolarizing signal in the ventral root of the spinal cord. Furthermore, reflex discharge patterns from DRG stimulation of a human fetus in the third trimester of development were similar to that of the pattern of a 3-4 day postnatal rat. The monosynaptic discharge reflex, which involves transmission of a sensory signal through the DRG, can be demonstrated during the late fetal period of most mammals and after birth. Specifically for rats, this reflex could be elicited in a basic form by E17.5. <ref name="PMID512959"/><br />
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These results demonstrate that even though the functionality of the DRG is not completely refined at birth, neurons within the DRG are still able to process sensory stimuli to some degree and convey an action potential during later stages of prenatal development.<br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of human embryonic development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant apoptosis following the migration and before full maturation.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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After migration of the NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The protein Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt-signalling and b-cantenin activity,the neurogenin transcription factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and SOX10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis, and without this signalling glial cells are absent in the DRG. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the migration and subsequent differentiation of cells in the DRG are the ErbB2 and ErbB3 molecules that are members of the ErbB receptor kinase family and that interact with neuregulin-1(NRG-1) and neuregulin-2(NRG-2). <ref name="PMID23403761"/> They are important in regulating and maintaining levels of DRG progenitors and in guiding the migratory peripheral paths of glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of the DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different formation patterns. The first population of cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on peripheral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on motor neurons for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases is during development, the expression of these receptors decreases significantly following neurogenesis and differentiation due to down-regulation of associated neurotrophins. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The SOX10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by '''[https://www.omim.org/entry/113505 brain-derived neurotrophic factor(BDNF)]''' and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that populate the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons in the DRG or significant apoptosis of the neurons in the DRG <ref name="PMID8208292"/>. <br />
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<small>''Note: Some of the terms in this section that are important proteins, transcription factors, or molecules in neuronal and glial development and growth in the DRG have been bolded and hyperlinked to <br />
'''[https://www.omim.org/ Online Mendelian Inheritance in Man]''', an online catalog of human genes and genetic disorders, in order to provide more information about the factor in question if necessary.<br />
''</small><br />
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===Axonal Targeting===<br />
Axonal projections of developing neurons begin to reach their target tissues between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> The axons of neurons in the DRG project to both their target tissues and an area of the spinal cord to transmit sensory signals into the CNS.<ref name="PMID9712660"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
'''[https://www.omim.org/entry/162030 Nerve Growth Factors (NGF)]''' are important regulators of specific dorsal-lateral axonal growth from the neurons in the DRG. Specifically with TrkA+ neurons, NGF signaling and receptor binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues without this activity. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins-3 and 4/5 also bind to tyrosine receptor kinases. <ref name="PMID11684666"/><br />
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Without the binding of these factors onto these specific receptors of developing neurons during the neurogenesis period in the DRG, neurons undergo excessive apoptosis and fail to mature. <ref name="PMID8982156"/>.<br />
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====Neurotrophin-3====<br />
'''[https://www.omim.org/entry/162660 Neurotrophin-3 (NT-3)]''' has been shown to be essential in driving growth towards target tissues in the majority of neurons and maintaining neuronal survival. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to a reduced concentration of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will have a reduced DRG neuronal volume compared to wild type mice. <ref name="PMID8982156"/> As NT-3 is important in driving growth,'''[https://www.omim.org/entry/600837 glial-derived neurotrophic factor (GDNF)]''' has been shown to suppress and restrict growth and branching to balance the activity of NT-3 through its direct downregulation of the neurotrophin.<ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors '''[https://www.omim.org/entry/601632 Brn3a]''' and '''[https://www.omim.org/entry/113725 Brn3b]''' are important regulators of axonal extension from specific neurons of the DRG into the spinal cord in order to transmit signals into the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5 for mice <ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not project into the dorsal horn, and similarly the axons of TrkC+ neurons do not reach the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly affect the expression and function of <br />
'''[https://www.omim.org/entry/151385 Runx1]''' and '''[https://www.omim.org/entry/600210 Runx3]''' signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the dorsal root entry zone of the spinal cord as early as E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID9100133"/><br />
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===Neuron Development===<br />
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Neuronal differentiation, following neural crest cell migration into the area of DRG development, requires specific signalling and gene expression patterns in order for neuronal precursors to mature into specific neuronal populations with different axonal targeting profiles and proliferation timelines. Specific tyrosine receptor kinase expression and neurotrophin signalling acts as one of the most distinct predictors of the future fate of a neuron. <ref name="PMID9728914"/><br />
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====Sox2 and Sox10====<br />
The '''[https://www.omim.org/entry/184429 SOX2]''' and '''[https://www.omim.org/entry/602229 SOX10]''' transcription factors play a major signalling role in the individual differentiation of neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
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SOX10 shows reduced expression in neurons once they have begun to differentiate due to downregulation, but it continues to be expressed in glial lineages past differentiation stages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1, which is a major transcription factor involved in neurogenesis. <ref name="PMID28253350"/> <br />
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SOX2 is required for neurogenesis, and deficiencies in SOX2 activity prevents neural crest cells from differentiating into neuronal, and to a less significant degree, glial lineages. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once neural crest cells reach their target migratory area of the DRG<ref name="PMID21549328"/> In glial cell lineages, SOX2 prevents immature Schwann cells from developing myelinating properties, and this gene inhibition prevents terminal differentiation and indirectly leads to enhanced proliferation. <ref name="PMID15695336"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration.<ref name="PMID9728914"/>Depending on which tyrosine receptor kinase the neuron expresses will affect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate and maintains growth and survival. <ref name="PMID9728914"/> The neurons that express high affinity '''[https://www.omim.org/entry/191315 TrkA]''' receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity '''[http://omim.org/entry/191316 TrkC]''' receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity '''[https://www.omim.org/entry/600456 TrkB]''' receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. Developing neurons show specific mRNA expression patterns for these three tyrosine kinase receptors. Patterning of the receptors was largely based on the stage of embryonic development and where migration ended within the developing DRG for these cells. <ref name="PMID8366358"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptors and proprioceptors. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the receptor tyrosine kinase '''[https://www.omim.org/entry/164761 Ret]''' during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. <ref name="PMID17553423"/> Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
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===Timeline of Neurogenesis Waves===<br />
Neurogenesis occur in the rostral-caudal direction. The neurogenesis waves represent the general timeframe during embryonic development when each population of sensory neurons begin to develop from precursors following neural crest cell migration. High expression of either the '''[https://www.omim.org/entry/601726 neurogenin-1(Ngn-1)]''' or '''[https://www.omim.org/entry/606624 neurogenin-2 (Ngn-2)]''' transcription factor generally acts as a reliable indicator of which neurogenesis wave is in effect. <ref name="PMID10398684"/>. This timeline represents the mouse model of neurogenesis and embryonic developmental days, and these days were converted into the relative human embryonic developmental days as a [https://embryology.med.unsw.edu.au/embryology/index.php/Models_of_Human_Development reference] <ref>Hill, M.A. (2018, October 16) Embryology Models of Human Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Models_of_Human_Development</ref><br />
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'''E9.5-E11 (Human: Day 22-30):''' The first wave of neural crest cell migration into the area of the DRG occurs during this period. Neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors emerge. This wave is mostly mediated by Ngn-2 expression. <ref name="PMID10398684"/>. These neurons will generally develop into the mechanoceptors and proprioceptors of the DRG <ref name="PMID25885041"/>. Ngn-2 expression ends around E10.5, but it overlaps slightly with the period of neuronal condensation into ganglion<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5 (Human: Day 28-44):''' The second wave of neurogensis overlaps with the first wave, and it leads to the initial development of neurons expressing high levels of NGF-specific TrkA receptors. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will generally develop into the nociceptors of the DRG. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and it is only expressed following migration and neuronal condensation into ganglion. <ref name="PMID10398684"/> <br />
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'''E12-E13 (Human: Day 36-42):''' The most rapid proliferation of neurons occurs during this period of neurogenesis. <ref name="PMID9728914"/> <br />
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'''E11-E15 (Human: Day 30-54):''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5 (Human: Day 44-55):''' TrkC+ and TrkA+ afferents begin to penetrate into the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ afferents projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5+ (Human: Day 60+): ''' Sensory neurons undergo maturation and concentration levels stabilize. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. Satellite glial cells, which are also important glial cells that arise during embryonic development, remain in the DRG. <ref name="PMID27058953"/> They play a role in controlling the environment surrounding neurons in the DRG, and specifically during the period of apoptosis during neurogenesis, they engulf the decaying material and clear out the excess waste.<ref name="PMID19915564"/> <br />
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The Schwann cell precursors and satellite cell precursors usually are derived from neural crest cells about 1.5 days following the beginning of neurogenesis. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
'''[https://www.omim.org/entry/142445 Neuregulin-1(NRG-1)]''' is an important signalling molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both '''[https://www.omim.org/entry/164870 ErbB2]''' and '''[https://www.omim.org/entry/190151 ErbB3]''' receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and helps initiate myelination interactions of the glial cells with peripheral neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, Notch signalling is reduced by Krox20 (Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 also acts as a required factor in neural crest cells differentiating into glial cell precursors<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration,and even continues beyond birth, for Schwann and satellite glial cells. <ref name="PMID11156606"/> Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheath protein in the peripheral nervous system. When SOX10 is active on the protein zero promoter, glial cells increase their production of this myelinating protein. Deficiencies in SOX10 can lead to a smaller DRG due to reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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====Krox20====<br />
'''[https://www.omim.org/entry/129010 Krox20]''', a gene that is homologous to Egr2, acts as another major transciptional regulator of myelination properties in immature Schwann cells. Schwann cells that express high levels Krox20 mature with myelinating properties due to the control of Krox20 on the expression of both myelin-associated genes and genes associated with the synthesis of glycolipids. <ref name="PMID1394999"/> Cells that do not express Krox20 concentrate in the DRG and increase the population of nociceptive neurons and non-myelinating glia. <ref name="PMID25885041"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days, and these days were converted into the relative human embryonic development days as a [https://embryology.med.unsw.edu.au/embryology/index.php/Models_of_Human_Development reference] <ref>Hill, M.A. (2018, October 16) Embryology Models of Human Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Models_of_Human_Development</ref>.<br />
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----<br />
<br />
'''E10.5 (Human: Day 28):''' Migration of neural crest cells that will differentiate into glial cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
----<br />
<br />
'''E12-E13 (Human: Day 36-42):''' Satellite glial cell precursors begin to differentiate from neural crest cells. <ref name="PMID27058953"/> Schwann cell precursors emerge from boundary cap neural crest cells that surround the dorsal root entry zone, as well as additional satellite cell precursors <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/><br />
<br />
----<br />
<br />
'''E14-E15 (Human: Day 48-54):''' Schwann cell precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
<br />
----<br />
<br />
'''E15-E16 (Human: Day 54-58):''' Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
----<br />
<br />
'''E15.5 (Human: Day 55): ''' Krox20 gene expression begins, along with expression of other factors and genes associated with myelinating properties, in immature Schwann cells. <ref name="PMID15322547"/> <br />
<br />
----<br />
<br />
'''E18.5+ (Human: Day 60+):''' Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
----<br />
<br />
==Adult Function/Tissue structure==<br />
The DRG is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/><br />
<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates, the DRG is a cluster of neurons located in the dorsal root of the spinal cord. It is a bulb-like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers. These cell bodies are oval in shape and are wrapped completely in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}. The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies. It also has microvilli arising from its cell bodies. Another feature of the DRG is the terminal dogiels nest, which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
<br />
Furthermore, the DRG has long axons, known as afferents, that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord. Lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root and are small in diameter, relaying pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root, which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Mechanisms==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG and its components. Some of the mechanisms that have been studied are briefly described below: <br />
<br />
===Signalling pathways===<br />
===='''Wnt'''====<br />
[[File:Canonical Wnt pathway.jpg|right|300px|thumb|wrap|Overview of the canonical Wnt pathway]]<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
<br />
β-catenin is an important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>.<br />
<br />
===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/>.<br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done through the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proportion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cells, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Illustration of Sox signalling pathway.jpg|right|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models <ref name="PMID11731238"/>. <br />
<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/>.<br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/>. Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/>.<br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is shown to cause disruptions in neurogenesis of Rbpj mutant mice, decreasing cell proliferation and increasing apoptosis <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also referred to as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
This disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
===Sjögren Syndrome===<br />
[[File:Sjogrens_syndrome_1.jpg||left|300px|thumb|embed|patient with sjogren syndrome,"(a and c) Photographs of the same patient. (b) Chronic purpuric eruption on pretibial area". ]]<br />
<br />
Sjögren Syndrome (SS) is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that are either poor or lack thereof, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Studies have shown that there is a large reduction in the sensory potential amplitudes, but towards the legs, there is no distal worsening gradient. When studies are done on the motor nerve conduction, and the distal motor amplitudes, there are no issues most of the time.<br />
<br />
Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord.MRI is commonly used in patients with chronic Sjögren Syndrome, showing that there is a hyper intense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. {{#pmid:27175675|PMID27175675}}<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|embed|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and DRG development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of DRG neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that ErbB3 and ErbB2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/>. ErbB3 signaling has also been shown to be required for the development of DRG neurons in zebrafish models, as the neural crest cells do not stop at the usual location of DRG formation when ErbB3 ligands are absent <ref name="PMID18599505"/>.<br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal cord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimics ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Dorsalateral''' - related to the back and side<br />
<br />
'''Dorsa aorta''' - paired embryological vessels which progress to form the descending aorta<br />
<br />
'''Epithelial-to mesenchymal transition (EMT)''' - a process where epithelial cells obtain migratory and invasive abilities and becomes mesenchymal stem cells, while losing cell polarity and cell-cell adhesion<br />
<br />
'''Neural crest cells''' - a group of cells arising from the ectoderm that differentiates into various cell lineages during the development of the embryo<br />
<br />
'''Schwann cells''' - a glial cell in the peripheral nervous system that wraps around the nerve fiber to forms the myelin sheaths<br />
<br />
'''ventro-lateral''' - related to the front and side<br />
<br />
'''ventro-medial''' - related to the front and to the middle<br />
<br />
==List of Abbreviations==<br />
<br />
'''AP''': Anterior-posterior<br />
<br />
'''BDNF''': Brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''': Epidermal Growth Factor<br />
<br />
'''EMT''': Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''': Nerve growth factor<br />
<br />
'''NGN''': Neurogenin<br />
<br />
'''NRG''': Neuregulin<br />
<br />
'''NRH''': Neurohgulins<br />
<br />
'''NT''': Neurotrophin <br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedgehog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
'''TRK''': Tyrosine Receptor Kinase<br />
<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358347
2018 Group Project 5
2018-10-16T01:28:48Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
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<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5:''' TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:''' Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important signalling molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5:''' Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:''' Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
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'''E15-E16:''' Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
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'''18.5+:''' Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
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==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
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==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
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===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
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In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
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β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
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===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
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Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
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Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
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===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
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Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
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Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
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===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
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[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
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===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
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===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
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The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
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===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
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==Disorders==<br />
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Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
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===Sensory Ganglionitis===<br />
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Sensory ganglionitis, also referred to as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
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These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
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===Sjögren Syndrome===<br />
Sjögren Syndrome (SS) is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that are either poor or lack thereof, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.<br />
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Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy. SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap. {{#pmid:27175675|PMID27175675}}<br />
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==Animal Models==<br />
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===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
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“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
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===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
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Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
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Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
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Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
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==Current Research (Labs)==<br />
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<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
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'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
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[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
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[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
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The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
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'''Dorsal root ganglion stimulation'''<br />
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Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
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The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
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[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
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'''DRG patch clamp studies'''<br />
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<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
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Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
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[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
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==Glossary==<br />
'''Abbreviations'''<br />
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'''AP''':anterior-posterior<br />
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'''BDNF''':brain-derived neurotrophic factor<br />
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'''BMP''': Bone Morphogenetic Protein<br />
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'''CCD''': Chronic Compression of DRG<br />
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'''CRPS''': Complex Regional Pain Syndrome<br />
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'''EGF''':Epidermal Growth Factor<br />
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'''EMT''':Epithelial to Mesencyhmal Transition<br />
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'''NGF''':Nerve growth factor<br />
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'''NRH''':Neurohgulins<br />
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'''SCS''': Spinal Chord Stimulation<br />
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'''SHH''': Sonic hedge hog<br />
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'''DRG''': Dorsal Root Ganglion<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358281
2018 Group Project 5
2018-10-16T00:31:28Z
<p>Z5229399: /* Sensory Ganglionitis */</p>
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=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
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<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
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==History==<br />
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Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
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'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
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'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
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'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
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==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
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Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
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===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5:''' TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:''' Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
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(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
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Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important signalling molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5:''' Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:''' Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
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'''E15-E16:''' Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
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'''18.5+:''' Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
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==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
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==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
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===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
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In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
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β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
<br />
===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also referred to as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
===Sjögren Syndrome===<br />
Sjögren Syndrome (SS) is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that are either poor or lack thereof, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.<br />
<br />
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy. SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap. {{#pmid:27175675|PMID27175675}}<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
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{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
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{{#pmid:21510873|PMID21510873}}<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358279
2018 Group Project 5
2018-10-16T00:31:02Z
<p>Z5229399: /* Sjögren Syndrome */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
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'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
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'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
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'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
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==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
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Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
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===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5:''' TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:''' Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
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(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
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Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important signalling molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5:''' Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:''' Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
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'''E15-E16:''' Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
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'''18.5+:''' Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
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==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
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==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
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===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
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In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
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β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
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===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
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Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
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Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
===Sjögren Syndrome===<br />
Sjögren Syndrome (SS) is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that are either poor or lack thereof, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.<br />
<br />
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy. SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap. {{#pmid:27175675|PMID27175675}}<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
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{{#pmid:21510873|PMID21510873}}<br />
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{{#pmid:11156606|PMID11156606}}<br />
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{{#pmid:21510873|PMID21510873}}<br />
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{{#pmid:25363691|PMID25363691}}<br />
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{{#pmid:24004948|PMID24004948}}<br />
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{{#pmid:12352981|PMID12352981}}<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358275
2018 Group Project 5
2018-10-16T00:30:37Z
<p>Z5229399: /* Sjögren Syndrome */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
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Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
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===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5:''' TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:''' Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
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(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
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Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important signalling molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5:''' Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:''' Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
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'''E15-E16:''' Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
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'''18.5+:''' Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
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==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
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==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
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===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
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In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
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β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
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===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
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Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
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Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
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===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
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Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
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Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
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===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
===Sjögren Syndrome===<br />
Sjögren Syndrome is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that are either poor or lack thereof, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.<br />
<br />
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy.16 SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap. {{#pmid:27175675|PMID27175675}}<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24682971|PMID24682971}}<br />
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{{#pmid:1292751|PMID1292751}}<br />
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{{#pmid:10398684|PMID10398684}}<br />
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{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}<br />
{{#pmid:27058953|PMID27058953}}<br />
{{#pmid:14716020|PMID14716020}}<br />
{{#pmid:23403761|PMID23403761}}<br />
{{#pmid:26365194|PMID26365194}}<br />
{{#pmid:8208292|PMID8208292}}<br />
{{#pmid:22682243|PMID22682243}}<br />
{{#pmid:22682243|PMID22682243}}<br />
{{#pmid:16793760|PMID16793760}}<br />
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{{#pmid:20004982|PMID20004982}}<br />
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{{#pmid:12051814|PMID12051814}}<br />
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{{#pmid:12573434|PMID12573434}}<br />
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{{#pmid:16429136|PMID16429136}}<br />
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{{#pmid:1358870|PMID1358870}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358273
2018 Group Project 5
2018-10-16T00:29:05Z
<p>Z5229399: /* Sjögren Syndrome */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5:''' TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:''' Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important signalling molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5:''' Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:''' Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
<br />
'''E15-E16:''' Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
<br />
'''18.5+:''' Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
<br />
===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
<br />
β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
<br />
===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
===Sjögren Syndrome===<br />
Sjögren Syndrome is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that are either poor or lack of, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.<br />
<br />
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy.16 SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap. {{#pmid:27175675|PMID27175675}}<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
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{{#pmid:21510873|PMID21510873}}<br />
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{{#pmid:11156606|PMID11156606}}<br />
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{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
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{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
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{{#pmid:14716020|PMID14716020}}<br />
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{{#pmid:26365194|PMID26365194}}<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358213
2018 Group Project 5
2018-10-15T21:17:16Z
<p>Z5229399: /* Disorders */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
<br />
'''18.5+:'''Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
<br />
===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
<br />
β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
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===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
===Sjögren Syndrome===<br />
Sjögren Syndrome is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that either poor or lack of, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.<br />
<br />
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy.16 SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap. {{#pmid:27175675|PMID27175675}}<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}<br />
{{#pmid:27058953|PMID27058953}}<br />
{{#pmid:14716020|PMID14716020}}<br />
{{#pmid:23403761|PMID23403761}}<br />
{{#pmid:26365194|PMID26365194}}<br />
{{#pmid:8208292|PMID8208292}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358211
2018 Group Project 5
2018-10-15T21:14:31Z
<p>Z5229399: /* Sjögren Syndrome */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
<br />
'''18.5+:'''Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
<br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
<br />
===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
<br />
β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
<br />
===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
===Sjögren Syndrome===<br />
Sjögren Syndrome is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that either poor or lack of, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.<br />
<br />
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy.16 SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap.<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}<br />
{{#pmid:27058953|PMID27058953}}<br />
{{#pmid:14716020|PMID14716020}}<br />
{{#pmid:23403761|PMID23403761}}<br />
{{#pmid:26365194|PMID26365194}}<br />
{{#pmid:8208292|PMID8208292}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358209
2018 Group Project 5
2018-10-15T21:13:20Z
<p>Z5229399: /* Sensory Ganglionitis */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
<br />
'''18.5+:'''Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
<br />
===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
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β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
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===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
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Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
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Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
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===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
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===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
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===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
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The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
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===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
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===Sensory Ganglionitis===<br />
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Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
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These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
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===Sjögren Syndrome===<br />
Sjögren Syndrome is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that either poor or lack of, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found.5–7 Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed.3,8 Most of the time, motor nerve conduction studies and distal motor amplitudes are normal.8 Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi.9 Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.10<br />
<br />
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women.11 It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy.16 SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap.<br />
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==Animal Models==<br />
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===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
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<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}<br />
{{#pmid:27058953|PMID27058953}}<br />
{{#pmid:14716020|PMID14716020}}<br />
{{#pmid:23403761|PMID23403761}}<br />
{{#pmid:26365194|PMID26365194}}<br />
{{#pmid:8208292|PMID8208292}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358203
2018 Group Project 5
2018-10-15T20:58:56Z
<p>Z5229399: /* Sensory Ganglionitis */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
<br />
'''18.5+:'''Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
<br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
<br />
===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
<br />
β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
<br />
===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. {{#pmid:27175675|PMID27175675}}<br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
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{{#pmid:16054851|PMID16054851}}<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358201
2018 Group Project 5
2018-10-15T20:58:11Z
<p>Z5229399: /* Sensory Ganglionitis */</p>
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<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
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{{Editing Links}}<br />
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=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
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<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
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Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
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'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
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'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
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'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
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==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
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Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
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===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
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(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
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Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
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'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
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'''18.5+:'''Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
<br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
<br />
===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
<br />
β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
<br />
===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID27175675"/><br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
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{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
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{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
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{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
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{{#pmid:21510873|PMID21510873}}<br />
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{{#pmid:10398684|PMID10398684}}<br />
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{{#pmid:25271163|PMID25271163}}<br />
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{{#pmid:19429784|PMID19429784}}<br />
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{{#pmid:21510873|PMID21510873}}<br />
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{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
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{{#pmid:11684666|PMID11684666}}<br />
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{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
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{{#pmid:19915564|PMID19915564}}<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358199
2018 Group Project 5
2018-10-15T20:57:07Z
<p>Z5229399: /* Sensory Ganglionitis */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
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'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
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==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
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Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
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===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
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(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
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Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
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'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
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'''18.5+:'''Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
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==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
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==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
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===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
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In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
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β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
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===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
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Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
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Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
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===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
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Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
<br />
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
<br />
'''BDNF''':brain-derived neurotrophic factor<br />
<br />
'''BMP''': Bone Morphogenetic Protein<br />
<br />
'''CCD''': Chronic Compression of DRG<br />
<br />
'''CRPS''': Complex Regional Pain Syndrome<br />
<br />
'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}<br />
{{#pmid:27058953|PMID27058953}}<br />
{{#pmid:14716020|PMID14716020}}<br />
{{#pmid:23403761|PMID23403761}}<br />
{{#pmid:26365194|PMID26365194}}<br />
{{#pmid:8208292|PMID8208292}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=358197
2018 Group Project 5
2018-10-15T20:51:12Z
<p>Z5229399: /* Sensory Ganglionitis */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
[[File:Dorsal_Root_Ganglia_Adult.jpg]]<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
'''''1811 -Charles Bell''''' <br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID14716020 "/> Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of DRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2. <ref name="PMID23403761"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells. <ref name="PMID26365194"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID9728914"/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. <ref name="PMID8208292"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model<ref name="PMID20534675"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. <ref name="PMID14699579"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the ganglia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation. Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E14-E15:''' Precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20 (Erg2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery. <ref name="PMID15322547"/><br />
<br />
'''18.5+:'''Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
[[File:drg_SKETCH.jpg|400px|thumb|embed| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}.<br />
<br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
Various signalling pathways and molecular factors contribute to the development of the DRG, some of which have been studied and highlighted below: <br />
<br />
===Signalling pathway===<br />
===='''Wnt'''====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex <ref name="PMID12356903"/>.<br />
<br />
β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation <ref name="PMID12473692"/>. The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta <ref name="PMID14716020"/><br />
<br />
===='''ErbB'''====<br />
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>.<br />
<br />
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation <ref name="PMID20832498"/>.<br />
<br />
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage <ref name="PMID12051814"/>, expansion and migration of Schwann cell precursor <ref name="PMID11056475 "/> and providing signals for myelination <ref name="PMID16129398"/>. Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival <ref name="PMID11056475"/><br />
<br />
===='''Notch signalling'''====<br />
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation <ref name="PMID16054851"/>. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/>. This is done by the process of lateral inhibition and lateral induction.<br />
<br />
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways <ref name="PMID9892564"/>. On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type <ref name="PMID9892564"/>. In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis <ref name="PMID10850492"/>. <br />
<br />
Activation of the Notch signalling has been demonstrated to elevate the proprotion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG <ref name="PMID17920293"/>. A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state <ref name="PMID16054851 "/>.<br />
<br />
===Transcription Factors===<br />
===='''Sry-related HMG box (Sox)'''====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
===='''Neurogenin'''====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate <ref name="PMID10398684"/>.<br />
<br />
===='''Runx'''====<br />
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade <ref name="PMID12485160"/>. The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression <ref name="PMID12573434"/><br />
<br />
The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/>. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons <ref name="PMID12352981"/> and in the survival and development of DRG neurons <ref name="PMID12093746"/> Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons <ref name="PMID16429136"/><br />
<br />
===='''Rbpj'''====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is demonstrated to cause disruptions in neurogenesis of Rbpj mutant mice while decreasing cell proliferation and increasing apoptosis as well <ref name="PMID21510873"/>.<br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
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Sensory ganglionitis, also called as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome. <br />
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These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
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==Animal Models==<br />
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===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
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“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
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===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
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Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
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Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres <ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest <ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
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Research has also demonstrated that erbb3 and erbb2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons <ref name="PMID15797019"/><br />
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==Current Research (Labs)==<br />
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<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
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'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
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[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
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[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
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The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
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'''Dorsal root ganglion stimulation'''<br />
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Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
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The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
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[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
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'''DRG patch clamp studies'''<br />
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<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media><br />
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Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
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[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
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==Glossary==<br />
'''Abbreviations'''<br />
<br />
'''AP''':anterior-posterior<br />
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'''BDNF''':brain-derived neurotrophic factor<br />
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'''BMP''': Bone Morphogenetic Protein<br />
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'''CCD''': Chronic Compression of DRG<br />
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'''CRPS''': Complex Regional Pain Syndrome<br />
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'''EGF''':Epidermal Growth Factor<br />
<br />
'''EMT''':Epithelial to Mesencyhmal Transition<br />
<br />
'''NGF''':Nerve growth factor<br />
<br />
'''NRH''':Neurohgulins<br />
<br />
'''SCS''': Spinal Chord Stimulation<br />
<br />
'''SHH''': Sonic hedge hog<br />
<br />
'''DRG''': Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}<br />
{{#pmid:27058953|PMID27058953}}<br />
{{#pmid:14716020|PMID14716020}}<br />
{{#pmid:23403761|PMID23403761}}<br />
{{#pmid:26365194|PMID26365194}}<br />
{{#pmid:8208292|PMID8208292}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357987
2018 Group Project 5
2018-10-15T12:25:01Z
<p>Z5229399: /* Disorders */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
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{{Editing Links}}<br />
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=Dorsal Root Ganglion=<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
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==History==<br />
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Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
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'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
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'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
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'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
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==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. [[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====Wnt====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes <ref name="PMID12356903"/>.<br />
<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
<br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is expected to inhibit Notch signalling when deleted <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Disorders==<br />
<br />
Disorders in the Dorsal Root Ganglion is generally grouped as degeneration in the sensory neutrons of the Dorsal Root Ganglion (DRG). They are commonly referred to as polyganglionopathies, ganglion-opathies, ganglioneuritis, or simpler sensory neuronopathies <br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
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{{#pmid:22375099|PMID22375099}}<br />
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{{#pmid:28242477|PMID28242477}}<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357983
2018 Group Project 5
2018-10-15T12:19:32Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
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{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
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<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
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<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. [[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====Wnt====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes <ref name="PMID12356903"/>.<br />
<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
<br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is expected to inhibit Notch signalling when deleted <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Disorders==<br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357977
2018 Group Project 5
2018-10-15T12:15:16Z
<p>Z5229399: /* Rat/Mouse Model= */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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<br />
===Glia Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. [[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====Wnt====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes <ref name="PMID12356903"/>.<br />
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====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
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====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
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===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
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[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
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====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is expected to inhibit Notch signalling when deleted <ref name="PMID21510873"/>.<br />
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====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
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====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
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==Abnormalities / Abnormal Development==<br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
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==Animal Models==<br />
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===Rat Model===<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357975
2018 Group Project 5
2018-10-15T12:14:24Z
<p>Z5229399: /* Animal Models */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
<br />
<br />
The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
<br />
===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
<br />
===Glia Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
<br />
(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
<br />
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. [[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====Wnt====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes <ref name="PMID12356903"/>.<br />
<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
<br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is expected to inhibit Notch signalling when deleted <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
===Rat/Mouse Model====<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
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Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357973
2018 Group Project 5
2018-10-15T12:11:35Z
<p>Z5229399: /* Animal Models */</p>
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<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
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=Dorsal Root Ganglion=<br />
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media><br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals, the dorsal root ganglia develops from the neural crest.The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo {{#pmid:15590743|PMID15590743}}. <br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. <ref name="PMID27130590"/><br />
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==History==<br />
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Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
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'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
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'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
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'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
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==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
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===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
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There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>:<br />
#A dorsolateral pathway between the ectoderm and the somites<br />
#A ventro-lateral pathway between and through the somites<br />
#A ventro-medial pathway between the neural tube and the posterior sclerotome<br />
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The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
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==Developmental Process==<br />
===Neural Crest Migration in Formation of the Dorsal Root Ganglion===<br />
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Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
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[[File:Neural Crest Migration.png|600px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/> <br />
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===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
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Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|left|'''Normal expression of neurogenins in Rbpj-deficient DRG:''' (A-L) Transverse sections through the upper neural tube (nt) and surrounding tissue of wild-type (WT) and Rbpj CKO with Ngn1 (A-F) and Ngn2 (G-L) mRNA probes at the indicated stages. Loss of Rbpj does not appear to affect the expression of neurogenins either in migrating NCCs at E9.5 and E10.0, or in post-migratory NCCs in the DRG at E10.0 and E10.5. Arrows in (A,B,G,H) point to a cluster of migrating NCCs, and those in (C-F,I-L) point to post-migratory NCCs condensed in the DRG located laterally to the neural tube. High magnification views of the areas delineated by black rectangles in panels (C-F,I,J) are shown at the bottom of each panel. Note that the signal of in situ hybridization is present in the cytoplasm, whereas the nuclei contain no signals. ]]<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glia Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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[[File:Neurogenesis and Gliogenesis Timeline.jpg|450px|thumb|baseline|'''Schematic representation of the different phases of Schwann cell development:''' Schematic images of transverse sections through the trunk of E9.0 (A), E10.5 (B), E12.5 (C), E14.5 (D) and E18.5 (E) embryos, and a longitudinal section through the postnatal sciatic nerve (F). Insets in C-F show transverse sections through the sciatic nerve.<br />
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(A) The migration of NCCs from the dorsal neural tube <br />
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves <br />
(C) The association of Schwann cell precursors with developing axons<br />
(D) The maturation of Schwann cell precursors into immature Schwann<br />
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells.<br />
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Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]]<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5''':Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
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==Adult Function/Tissue structure==<br />
The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> It is functional immediately following birth.<br />
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In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. [[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
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Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.<br />
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==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====Wnt====<br />
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species <ref name="PMID22682243"/> and binds to transmembrane Frizzled Receptors (FZD) to activate two main types of signalling cascades, the canonical Wnt/β-catenin signalling pathway and the non-canonical signalling pathway <ref name="PMID16793760"/>. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) <ref name="PMID18848778"/> and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration <ref name="PMID20004982"/>.<br />
<br />
In the canonical Wnt/β-catenin signalling pathway, the binding of Wnt with FZD receptor activates the scaffold protein Dishevelled (Dvl) and results in the dissociation of a multiprotein complex involved in the degradation of β-catenin <ref name="PMID25234280"/>. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes <ref name="PMID12356903"/>.<br />
<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
<br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||200px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed, as seen in mouse models. <ref name="PMID11731238"/> <br />
<br />
[[File:Illustration of Sox signalling pathway.jpg|left|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]]<br />
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions <ref name="PMID19747562"/>, The initial binding of a second partner protein on the gene of interest is required before the pairing of the functional Sox-binding site can be made to induce gene expression, where binding a single Sox protein alone does not promote transcriptional activation or repression <ref name="PMID1358870"/>. Once the Sox-partner complex is established, it can serve as a stimulus for the activation of the gene of another transcription factor, which later serves as a partner for the Sox protein further down the signalling cascade <ref name="PMID24086078"/>. This is seen in the development of Schwann cells from the neural crest, where Sox10 interacts with Pou3f1/2 partner factor to form a complex that expresses the subsequent target gene Egr2, which regulates myelin genes and prevents proliferation when the Schwann cells differentiates <ref name="PMID17325040"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is expected to inhibit Notch signalling when deleted <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. The L4/L5 intervertebral foraminal is exposed, and implantation of steel rods will be done unilaterally. The lumbar dorsal root ganglion will then be chronically compressed via 1 rod per vertebra. Compression is then done to simulate conditions as spinal canal narrowing in the form of laterally herniated disc. Implantation in the intraforminal would result in some neuronal somal hyper excitability and action potentials that causes an increase in the sensitivity to pain. This helps in providing an animal model that replicates radicular pain - a type of pain that radiates into the lower extremities along the spinal nerve root {{#pmid:23054639|PMID23054639}}<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
<br />
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media><br />
<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}<br />
{{#pmid:27130590|PMID27130590}}<br />
{{#pmid:11731238|PMID11731238}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357689
2018 Group Project 5
2018-10-15T05:14:03Z
<p>Z5229399: /* Animal Models */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
<br />
===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> <br />
<br />
SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/>SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
<br />
Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
<br />
[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive.<br />
<br />
==Tissue Structure==<br />
<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
<br />
[[File:Structure of DRG in Sox10-deficient mice.jpg||400px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain. {{#pmid:23054639|PMID23054639}}<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
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{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
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{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357683
2018 Group Project 5
2018-10-15T05:11:18Z
<p>Z5229399: /* Animal Models */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
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{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
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<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
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[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
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[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as an intermediate state of neural crest cell differentiation into the neurons and glial cells that will comprise the DRG. The Sox10 transciption factor acts on these progenitors derived from neural crest, and its signalling contributes to the differentiation of the neural crest cells first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
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===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/> Neurons that are primarily involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but they branch into deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====Neurotrophin-3====<br />
Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> <br />
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SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/>SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. <br />
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Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. <ref name="PMID10398684"/> <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis <ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5''': TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E15-E16:'''Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
<br />
[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. <ref name="PMID20534675"/><br />
<br />
==Tissue Structure==<br />
<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
<br />
[[File:Structure of DRG in Sox10-deficient mice.jpeg||400px|thumb|wrap|Structure of DRG in Sox10-deficient mice]]<br />
<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
===Sensory Ganglionitis===<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain. <ref name="PMID23054639"/><br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357677
2018 Group Project 5
2018-10-15T05:09:34Z
<p>Z5229399: /* Sensory Ganglionitis */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then into glia. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin is associated with in development. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
<br />
===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/>Neurons that are involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) and are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====NT-3====<br />
NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors, of the DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling and receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and Sox10 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 also play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. Sox2 can engage with the promoters bHLH transcription factors, which include Ngn-1 and Ngn-2. SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but Sox2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differntiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of neuron begins to develop following neural crest cell migration and each are structured and moderated by different transcription factors,which include either high expression of neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing BDNF specific TrkB and NT-3 specific TrkC. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis NGF specific TrkA, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia <ref name="PMID10398684"/>. <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis<ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents entering projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both erbB2 and erbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor leads to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into glial cells and their progenitors<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E15-E16:'''Immature Schwann cells develop from schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
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==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
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[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. <ref name="PMID20534675"/><br />
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==Tissue Structure==<br />
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<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
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====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
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====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
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====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
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====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
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==Abnormalities / Abnormal Development==<br />
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===Sensory Ganglionitis===<br />
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[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
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Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
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==Animal Models==<br />
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“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
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Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
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As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
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===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
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Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
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==Current Research (Labs)==<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
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[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
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[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
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The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
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'''Dorsal root ganglion stimulation'''<br />
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Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
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The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
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[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
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'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357675
2018 Group Project 5
2018-10-15T05:09:17Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then into glia. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin is associated with in development. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
<br />
===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/>Neurons that are involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) and are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====NT-3====<br />
NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors, of the DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling and receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and Sox10 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 also play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. Sox2 can engage with the promoters bHLH transcription factors, which include Ngn-1 and Ngn-2. SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but Sox2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differntiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of neuron begins to develop following neural crest cell migration and each are structured and moderated by different transcription factors,which include either high expression of neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing BDNF specific TrkB and NT-3 specific TrkC. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis NGF specific TrkA, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia <ref name="PMID10398684"/>. <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis<ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents entering projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both erbB2 and erbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor leads to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into glial cells and their progenitors<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
<br />
[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. <ref name="PMID20534675"/><br />
<br />
==Tissue Structure==<br />
<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
=Sensory Ganglionitis=<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
<br />
As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357673
2018 Group Project 5
2018-10-15T05:08:39Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then into glia. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin is associated with in development. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
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===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/>Neurons that are involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) and are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====NT-3====<br />
NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors, of the DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling and receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and Sox10 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 also play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. Sox2 can engage with the promoters bHLH transcription factors, which include Ngn-1 and Ngn-2. SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but Sox2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differntiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of neuron begins to develop following neural crest cell migration and each are structured and moderated by different transcription factors,which include either high expression of neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
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<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing BDNF specific TrkB and NT-3 specific TrkC. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis NGF specific TrkA, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia <ref name="PMID10398684"/>. <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis<ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5''': TrkC+ and TrkA+ afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents entering projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both erbB2 and erbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor leads to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into glial cells and their progenitors<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E15-E16:'''Immature Schwann cells develop from schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
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==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
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[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. <ref name="PMID20534675"/><br />
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==Tissue Structure==<br />
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<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
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==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
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====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
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====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
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====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
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====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
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====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
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==Abnormalities / Abnormal Development==<br />
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[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
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Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
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==Animal Models==<br />
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“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
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Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
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As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
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===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
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Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
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Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
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==Current Research (Labs)==<br />
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'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
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[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
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[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
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The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
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'''Dorsal root ganglion stimulation'''<br />
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Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
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The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357671
2018 Group Project 5
2018-10-15T05:08:20Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then into glia. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin is associated with in development. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
<br />
===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/>Neurons that are involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) and are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====NT-3====<br />
NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors, of the DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling and receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and Sox10 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 also play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. Sox2 can engage with the promoters bHLH transcription factors, which include Ngn-1 and Ngn-2. SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but Sox2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differntiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of neuron begins to develop following neural crest cell migration and each are structured and moderated by different transcription factors,which include either high expression of neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing BDNF specific TrkB and NT-3 specific TrkC. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis NGF specific TrkA, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia <ref name="PMID10398684"/>. <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis<ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents entering projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both erbB2 and erbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor leads to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into glial cells and their progenitors<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
<br />
[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. <ref name="PMID20534675"/><br />
<br />
==Tissue Structure==<br />
<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
<br />
==Animal Models==<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
<br />
As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357669
2018 Group Project 5
2018-10-15T05:08:01Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
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Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
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The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
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Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
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Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
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==Neuronal and Glial Development and Growth==<br />
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Progenitor cells, also known as precursor cells, act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then into glia. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
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TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin is associated with in development. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
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===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/>Neurons that are involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
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====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) and are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
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====NT-3====<br />
NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors, of the DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
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====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
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Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
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===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling and receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
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====Sox2 and Sox10====<br />
The SOX2 and Sox10 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 also play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. Sox2 can engage with the promoters bHLH transcription factors, which include Ngn-1 and Ngn-2. SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but Sox2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
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====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differntiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
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It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
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TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
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===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of neuron begins to develop following neural crest cell migration and each are structured and moderated by different transcription factors,which include either high expression of neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
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[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
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'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing BDNF specific TrkB and NT-3 specific TrkC. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
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'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis NGF specific TrkA, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia <ref name="PMID10398684"/>. <br />
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'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
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'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis<ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
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'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
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'''E13.5-E15.5''': TrkC+ and TrkA+ afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents entering projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
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'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
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===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
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The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
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====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both erbB2 and erbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
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====Sox10====<br />
Even though the SOX10 transcription factor leads to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into glial cells and their progenitors<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
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===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
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'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
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'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
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'''E15-E16:'''Immature Schwann cells develop from schwann cell precursors. <ref name="PMID19525946"/><br />
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'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
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==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
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[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
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There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. <ref name="PMID20534675"/><br />
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==Tissue Structure==<br />
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In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
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==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
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====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
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====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
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====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
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====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
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====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
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==Abnormalities / Abnormal Development==<br />
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Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
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“[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]”<br />
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Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. <ref name="PMID24682971"/><br />
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==Animal Models==<br />
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“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
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Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
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As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
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===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
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Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
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Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
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==Current Research (Labs)==<br />
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'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
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[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
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[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
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The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
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'''Dorsal root ganglion stimulation'''<br />
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Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
{{#pmid:20399766|PMID20399766}}<br />
{{#pmid:14699579|PMID14699579}}<br />
{{#pmid:19535578|PMID19535578}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:22326227|PMID22326227}}<br />
{{#pmid:23701859|PMID23701859}}<br />
{{#pmid:19387688|PMID19387688}}<br />
{{#pmid:12352981|PMID12352981}}<br />
{{#pmid:10719890|PMID10719890}}<br />
{{#pmid:7514502|PMID7514502}}<br />
{{#pmid:11724954|PMID11724954}}<br />
{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_disorder.jpg&diff=357665
File:Dorsal Root Ganglion disorder.jpg
2018-10-15T05:06:37Z
<p>Z5229399: /* Copyright */</p>
<hr />
<div>==Legend==<br />
<br />
===Reference===<br />
{{#pmid:24682971}}<br />
<br />
===Copyright===<br />
© 2014 American Academy of Neurology<br />
<br />
{{Student image 2018}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=357663
2018 Group Project 5
2018-10-15T05:05:46Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
In the early embryo-genesis of humans and most mammals the dorsal root ganglia develops from the neural crest. The neural crest can be described as a transient structure found in vertebrates which gives rise to non-neuronal cell types such as, smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Dorsal Root Ganglion also referred to as the spinal ganglia or posterior root ganglia is a cluster of neurons found in the dorsal root of the spinal nerve. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. The cells found in the ganglion develop from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
<br />
Below is a timeline that list the important figures who have made contributions to the science of medicine and anatomy that lead up to the discovery of the dorsal root and eventually the ganglion within it .<br />
[[File:François Magendie.jpg|thumb|100px|[[François Magendie]]]][[File:CharlesBell001.jpg|thumb|100px|[[Charles Bell]]]][[File:Johannes Mueller.jpg|thumb|100px|[[Johannes Peter Müller]]]]<br />
<br />
<br />
'''''1811 -Charles Bell'''''<br />
First to discover that spinal nerves had two roots, one in the back and one in the front .With this in mind he conducted experiments on dead rabbits through dissection and found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were not present {{#pmid:21267589|PMID21267589}}. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root{{#pmid:27494015|PMID27494015}}.From this Bell concluded that the roots shared different functions ,the anterior root as nerves of "motion" and posterior or dorsal root as nerves of "sense"<br />
.Bell mentions these discoveries in a pamphlet he wrote to a short list of people including friends and students which begins the controversy on Bells claim to the discovery of the spinal nerve roots i.e the dorsal root, known as the Bell-Magendie law.<br />
<br />
<br />
'''''1822-Francois Magendie''''' Claims the discovery of which the anterior roots of the spinal cord control movement and the dorsal roots of the spinal cord control sensation {{#pmid:18447728|PMID18447728}}.Magendies work for most is considered to be a continuation of Bells work, magendie sought to discover more about each roots function since the dorsal roots function was not present through Bell's experiments. Therefore, Magendie did his experiments with live puppies am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"{{#pmid:27494015|PMID27494015}}.<br />
<br />
'''''1830s -Johannes Peter Müller'''''-] Was also an important figure in the discovery of the dorsal root because he unlike Bell published the work in time and developed a complete reproducible experiment that was not entirely cruel like Magendie . Muller repeated Magendies and Bells experimental procedures on frogs and the results were in line with both Magendie's and Bell's, that the dorsal root is sensory and anterior root is motor.<br />
<br />
==Embryonic Origins==<br />
Origins of the dorsal root ganglion can be traced back to the neural crest, which is made up of multi-potent cells emerging from the non-neural ectoderm and neural ectoderm. The neural crest cells (NCCs) arise along the stretch of the anterior-posterior (AP) axis, generating 4 different types of tissues at different regions of the axis. These tissues are namely the cranial, cardiac, vagal and trunk neural crest respectively <ref name="PMID28287247"/>. <br />
<br />
===Stages of Trunk Neural Crest Development===<br />
The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion <ref name="PMID19429784"/>. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites <ref name="PMID20399766"/>. The structure of the somite is responsible for regulating the migration and differentiation of NCCs by serving as physical barriers, activators for migration and signalling initiators <ref name="PMID28287247"/><br />
<br />
There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome <ref name="PMID20399766"/>. The pathway taken by the trunk NCCs determines the structure that they will contribute to. Those that travel in the intersomitic space between epithelial somites will eventually reach the dorsal aorta and end up as neurons and gila of the sympathetic ganglia while other trunk NCCs that remain within the sclerotome would combine to establish the sensory neurons, gila of the dorsal root ganglia and Schwann cells of the ventral roots <ref name="PMID15590743"/><br />
<br />
In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.<br />
<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5 <ref name="PMID21510873"/>. Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the dorsal root ganglion(DRG) cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/> <br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
[[File:Neural Crest Migration.png|300px|thumb|left|Illustration of a transverse section of the neural tube at E9, E10 and E11.5. The cells that contribute to the DRG are labeled in red.]]<br />
<br />
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/><br />
<br />
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/> <br />
<br />
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/><br />
<br />
==Neuronal and Glial Development and Growth==<br />
<br />
Progenitor cells, also known as precursor cells, act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then into glia. They are influenced by the enhancer sox10E1 <ref name="PMID28287247"/>.<br />
<br />
TrkA+ neurons, which compromise developing nociceptors and are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB+/TrkC+ neurons, which compromise developing mechanoreceptors and proprioceptors and are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, <ref name="PMID12031277 "/> act as the major classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons.<ref name="PMID24668479"/>. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin is associated with in development. <ref name="PMID12031277"/>. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. <ref name="PMID11731238"/><br />
<br />
===Axonal Targeting===<br />
Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. <ref name="PMID12031277"/>Neurons that are involved in nociception target areas of the dorsal horn. Neurons that are primarily involved in mechanoreception also target the dorsal horn, but deeper layers of the laminae. On the other hand, neurons that are involved in proprioception target the ventral horn via a pathway through the dorsal horn. <ref name="PMID12352981"/> <br />
<br />
====Nerve Growth Factors====<br />
Nerve Growth Factors(NGF) and are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. <ref name="PMID10719890"/> Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. <ref name="PMID11684666"/> Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. <ref name="PMID8982156"/>. <br />
<br />
====NT-3====<br />
NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors, of the DRG. <ref name="PMID7514502"/> Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception <ref name="PMID7514502"/>. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/> As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. <ref name="PMID11724954"/><br />
<br />
====Brn3a and Brn3b====<br />
Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5<ref name="PMID22326227"/>. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets<ref name="PMID22326227"/>.<br />
<br />
Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. <ref name="PMID12352981"/><br />
<br />
===Neuron Development===<br />
In a review in ''Cell and Tissue Research'' on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling and receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.<ref name="PMID19387688"/> <br />
<br />
====Sox2 and Sox10====<br />
The SOX2 and Sox10 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 also play a regulatory role in the condensing of neurons into the ganglia of the DRG.<ref name="PMID21549328"/> SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. <ref name="PMID11731238"/> Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron. Sox2 can engage with the promoters bHLH transcription factors, which include Ngn-1 and Ngn-2. SOX10 also can directly affect the expression of Ngn-1. <ref name="PMID28253350"/> It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but Sox2 is expressed again once these neural crest cells reach their target migratory area of the DRG.<ref name="PMID21549328"/><br />
<br />
====Tyrosine Receptor Kinases====<br />
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling. <ref name="PMID8730777"/> The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differntiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons. <ref name="PMID8730777"/><br />
<br />
It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. <ref name="PMID9728914"/><br />
<br />
TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. <ref name="PMID20534675"/> TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.<ref name="PMID20534675"/> Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. <ref name="PMID12352981"/><br />
<br />
===Timeline of Neurogenesis Waves===<br />
These waves occur rostral-caudally. These neurogenesis waves represents when each type of neuron begins to develop following neural crest cell migration and each are structured and moderated by different transcription factors,which include either high expression of neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) <ref name="PMID10398684"/>. This timeline represents mouse model of neurogenesis and embryonic developmental days.<br />
<br />
[[File:Ngn1 and Ngn2 in DRG development.png|300px|thumb|right|This figure compares of the concentration of cells expressing Ngn-1 and Ngn-2 in the DRG between wild-type and Rbpj knock out mice at E10.0 and E10.5. This figure demonstrates that loss of Rbpj signalling function does not affect neurogenin activity either in the migratory phase of neural crest cells at E9.5 and E10.0 or in post-migratory phase of neural crest cells at E10.0 and E10.5 within the DRG. The arrows indicate migrating neural crest cells or post-migratory neural crest cells condensed in the DRG.]]<br />
<br />
<br />
'''E9.5-E11:''' The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing BDNF specific TrkB and NT-3 specific TrkC. This wave is mostly mediated by Ngn-2. <ref name="PMID10398684"/>. These neurons will develop into mechanoceptive and proprioceptive neurons <ref name="PMID25885041"/>. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure<ref name="PMID21510873"/>. <br />
<br />
'''E10.5-13.5:''' The second wave overlaps with the first wave, and it leads to the neurogenesis NGF specific TrkA, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. <ref name="PMID10398684"/>. These neurons will develop into nociceptive neurons. <ref name="PMID25885041"/>. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia <ref name="PMID10398684"/>. <br />
<br />
'''E12-E13:''' The most rapid proliferation of neurons during the period of neurogenesis. <ref name="PMID12031277"/>. <br />
<br />
'''E12.5-E15.5:''' A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis<ref name="PMID24884373"/>. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. <ref name="PMID9361276"/>. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. <ref name="PMID25885041"/> Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. <ref name="PMID15322547"/> <br />
<br />
'''E11-E15:''' Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. <ref name="PMID19915564"/><br />
<br />
'''E13.5-E15.5''': TrkC+ and TrkA+ afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents entering projecting into the ventral horn and TrkA+ projecting into the dorsal horn. <ref name="PMID23701859"/> <br />
<br />
'''E18.5:'''Sensory neurons begin to undergo maturation. <ref name="PMID22326227"/><br />
<br />
===Glial Development===<br />
Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/>. Satellite cells, which are also important DRG glial cells, remain in the glia. <br />
<br />
The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. <ref name="PMID21510873"/>. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors <ref name="PMID19525946"/>.<br />
<br />
====NRG-1====<br />
Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. <ref name="PMID11156606"/> NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both erbB2 and erbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. <ref name="PMID19535578"/> Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset <ref name="PMID19525946"/>.<br />
<br />
====Sox10====<br />
Even though the SOX10 transcription factor leads to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into glial cells and their progenitors<ref name="PMID21510873"/>. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. <ref name="PMID11156606"/> Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis <ref name="PMID11641219"/>. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. <ref name="PMID10757804"/><br />
<br />
===Timeline of Gliogenesis===<br />
This timeline represents mouse model of gliogenesis and embryonic developmental days.<br />
<br />
'''E10.5''':Differentiation of glial cells begins from neural crest cells. <ref name="PMID23826407"/> <br />
<br />
'''E12-E13:'''Schwann cell precursors emerge from boundary cap cells. <ref name="PMID19525946"/> Their proliferation is maintained through NRG-1 activity. <ref name="PMID19535578"/> <br />
<br />
'''E15-E16:'''Immature Schwann cells develop from schwann cell precursors. <ref name="PMID19525946"/><br />
<br />
'''E15.5:''' Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. <ref name="PMID15322547"/><br />
<br />
==Adult Function==<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. <ref name="PMID22052556"/><br />
<br />
[[File:Dorsal Root Ganglia Adult.jpg|300px|thumb|right|A diagram of a cross section of an adult human spinal cord.]]<br />
<br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/> The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. <ref name="PMID20534675"/><br />
<br />
==Tissue Structure==<br />
<br />
<br />
In vertebrates the Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs){{#pmid:29729299|PMID:29729299}}.The SGCs have a laminar and irregular shape with microvilli expansions for increased surface area. The DRG neurons are pseudo-uni-polar in shape, several centimeters long and contain thousands of cell bodies it also has microvilli arising from its cell bodies .Another feature of the DRG is the terminal dogiels nest ,which are endings of sympathetic axons that resemble the shape of a plexus or nest that surrounds individual DRG neurons{{#pmid:29729299|PMID:29729299}}. <br />
Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.Lastly .[[File:drg_SKETCH.jpg|400px|thumb|wrap| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
==Signalling Pathways and Molecular Factors==<br />
===Signalling pathway===<br />
====ErbB====<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
====Notch signalling====<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/> This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types <ref name="PMID16054851"/><br />
===Transcription Factors===<br />
====Sry-related HMG box (Sox)====<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 <ref name="PMID16039883"/>, of which Sox10 plays the most crucial role in the development of the DRG. In the early stages of human development, Sox10 gene is preferentially exhibited in neural crest derivatives that establishes the peripheral nervous system and is found to be strongly expressed in both the DRG and the spinal nerves linked to it <ref name="PMID9720918"/>. In the absence of Sox10, the size of the DRG were significantly smaller, conforming to a longitudinal shape as compared to having a rounded shape, and the absence of a basement membrane separating the DRG and surrounding tissue can be observed <ref name="PMID11731238"/>.<br />
<br />
====Rbpj====<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
====Neurogenin====<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
====Glial cell-line-derived neurotrophic factor (GDNF)====<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
====Runx====<br />
Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons <ref name="PMID16446142"/><br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg|300px|Thumb|right|]]”<br />
<br />
Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. <br />
<br />
Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
==Animal Models==<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
<br />
As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
<br />
===Zebrafish Model===<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]]<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||300px|thumb|right|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
==Current Research (Labs)==<br />
<br />
'''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing {{#pmid:22375099|PMID22375099}}<br />
. This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." {{#pmid:22375099|PMID22375099}}<br />
.<br />
<br />
'''Dorsal root ganglion stimulation'''<br />
<br />
Over the past few years there has been profound research studies on dorsal root ganglion and its importance as a neuromodulation of pain, such research has introduced a new therapy for those suffering from Complex regional pain syndrome (CRPS) and other chronic pain conditions. Previously, the recommended treatment therapy for CRPS was spinal chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."{{#pmid: 28621025|PMID28621025}}. Which introduces a new treatment therapy known as DRGS or dorsal root ganglion stimulation, as the name suggest this approach understands the importance of DRG and therefore specifically targets the DRG in those with chronic pain. <br />
<br />
The research ''DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series'' {{#pmid: 28621025|PMID28621025}} wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .<br />
<br />
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation]<br />
<br />
'''DRG patch clamp studies'''<br />
<br />
Patch clamp studies have been important in furthering scientists understanding of the peripheral nervous system ,which has commonly been done through the utilization of dissociated DRG neurons from adult rats ''in vivo'' . However, through the use of dissociated DRG neurons there are unwanted side effects to this procedure such as alterations in neuronal properties and "dissociated neuron preparations cannot fully represent the microenvironment of the DRG"{{#pmid:27768031|PMID27768031}} due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ''ex vivo'' patch clamp procedure which mimicks ''in vivo'' conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"{{#pmid:27768031|PMID27768031}} . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" {{#pmid:27768031|PMID27768031}} . Provided below is a link to the research lab and the video on this procedure.<br />
<br />
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure]<br />
<br />
==Glossary==<br />
'''Abbreviations'''<br />
<br />
AP:anterior-posterior<br />
<br />
BMP: Bone Morphogenetic Protein<br />
<br />
CCD: Chronic Compression of DRG<br />
<br />
CRPS: Complex Regional Pain Syndrome<br />
<br />
EGF:Epidermal Growth Factor<br />
<br />
EMT:Epithelial to Mesencyhmal Transition<br />
<br />
NGF:Nerve growth factor<br />
<br />
NRH:Neurohgulins<br />
<br />
SCS: Spinal Chord Stimulation<br />
<br />
SHH: Sonic hedge hog<br />
<br />
DRG: Dorsal Root Ganglion<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}<br />
{{#pmid:28287247|PMID28287247}}<br />
{{#pmid:19429784|PMID19429784}}<br />
{{#pmid:16054851|PMID16054851}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:20534675|PMID20534675}}<br />
{{#pmid:17921861|PMID17921861}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:10757804|PMID10757804}}<br />
{{#pmid:8730777|PMID8730777}}<br />
{{#pmid:11684666|PMID11684666}}<br />
{{#pmid:9728914|PMID9728914}}<br />
{{#pmid:8982156|PMID8982156}}<br />
{{#pmid:9361276|PMID9361276}}<br />
{{#pmid:25885041|PMID25885041}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:25363691|PMID25363691}}<br />
{{#pmid:19915564|PMID19915564}}<br />
{{#pmid:19525946|PMID19525946}}<br />
{{#pmid:15322547|PMID15322547}}<br />
{{#pmid:12031277|PMID12031277}}<br />
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{{#pmid:19535578|PMID19535578}}<br />
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{{#pmid:12352981|PMID12352981}}<br />
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{{#pmid:28253350|PMID28253350}}<br />
{{#pmid:23826407|PMID23826407}}<br />
{{#pmid:11641219|PMID11641219}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=354349
2018 Group Project 5
2018-09-18T01:30:43Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
=Introduction=<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
=History=<br />
=Embryonic Origins=<br />
==Early Development==<br />
In the trunk of the embryo, a small number of neural crest cells (NCCs) migrate ventrally through the dorsal anteriorsclerotome, travelling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination. NCCs undergoes a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>.<br />
<br />
=Developmental Process=<br />
==Neural Crest Migration in Formation of the DRG==<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development through the anterior somite. Depending on where these cells cease their migratio will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites, lateral to the neural tube. <ref name="PMID15590743"/>. Both populations of cells, those that will develop into the Schwann cells and those that will develop into DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/>Boundary cap neural crest stem cells are some of the transient cells that give rise to the neurons and glia of the DRG.<ref name="PMID24884373"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. The multipotent Sox10+ and Kit-/Kit+ cells usually differentiate into neurons or glias during later stages following migration. <ref name="PMID24273191"/> TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. <ref name="PMID20017208"/> . These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. These transcription factors act as some of the first factors in signaling neurogenesis in the DRG, which marks the beginning of differentiation.<ref name="PMID24004948"/> Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>. Ngn2 leads to the first initiation of neurogenesis. <ref name="PMID20017208"/><br />
<br />
Many receptor kinases also aid in the migration and formation of DRG, specifically ErbB family with erbb2 and erbb3.<ref name="PMID24004948"/><br />
<br />
Neural Crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, lead to the generation of the TrkB and TrkC neurons. The second population, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, leads to the generation of TrkA neurons in this area. <ref name="PMID20017208"/><br />
<br />
==Neuron Development==<br />
The SOX2 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the Dorsal Root Ganglion. <ref name="PMID21549328"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neurons. SOX2 is thought to be bound to the progenitors NGN1 and MASH1 via a promoter region. <ref name="PMID21549328"/><br />
<br />
==Glial Development==<br />
Schwaan cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, schwaan cell precursors are derived from neural crest cells. <br />
Schwaan cells also have the capacity to derive melanocytes through schwaan to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/> <br />
<br />
=Adult Function=<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. <ref name="PMID25271163"/> Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/> <br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes.<br />
<ref name="PMID22052556"/><br />
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensations. For instance, the A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. <ref name="PMID25271163"/><br />
<br />
=Tissue Structure=<br />
<br />
The Dorsal root ganglion structure is less defined by its shape but by its function. The dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord . They have long axons known as afferents that are long so they can extend from dendrites on the skin to other tissues and organs throughout the body such as muscles,tendons,joints then to the brain. DRG neurons are psuedo-unipolar in shape, is several centimeters long and contains several cell bodies .<br />
<br />
[[File:drg_SKETCH.jpg|400px|thumb|right| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
=Molecular Mechanisms / Factors / Genes=<br />
==Transcription Factors==<br />
===Sry-related HMG box (Sox)===<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. The expression of ErbB3 is regulated by the transcription factor Sox10 and its level is consistently maintained throughout the period of neural crest cell migration <ref name="PMID11156606"/>. Sox10 is also widely expressed in the dorsal root ganglia as well as its surrounding spinal nerves <ref name="PMID9720918"/><br />
<br />
===Rbpj===<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
===Neurogenin===<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are notably expressed during neural crest migration and early dorsal root gangliogenesis. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
===Glial cell-line-derived neurotrophic factor (GDNF)===<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
===Runx===<br />
<ref name="PMID16446142"/>.<br />
<br />
==Signalling pathway==<br />
===ErbB===<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
===Notch signalling===<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/><br />
<br />
=Abnormalities / Abnormal Development=<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg|400px]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. <br />
<br />
Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
=Animal Models=<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies has been carried out to display these problems in animals. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This models exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra, to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
<br />
As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
<br />
==Zebrafish Model==<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|left|Neural crest migration and somite development in zebrafish.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||400px|thumb|left|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
=Current Research (Labs)=<br />
<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|400px|thumb|left|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing ( 2012 Sapunar et al). This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." ( 2012 Sapunar et al).<br />
<br />
=Glossary=<br />
<br />
<br />
<br />
<br />
<br />
=Reference List=<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}<br />
{{#pmid:25271163|PMID25271163}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=354321
2018 Group Project 5
2018-09-17T22:24:58Z
<p>Z5229399: /* Animal Models */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
=Introduction=<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
=History=<br />
=Embryonic Origins=<br />
==Early Development==<br />
In the trunk of the embryo, a small number of neural crest cells (NCCs) migrate ventrally through the dorsal anteriorsclerotome, travelling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination. NCCs undergoes a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>.<br />
<br />
=Developmental Process=<br />
==Neural Crest Migration in Formation of the DRG==<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development through the anterior somite. Depending on where these cells cease their migratio will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites, lateral to the neural tube. <ref name="PMID15590743"/>. Both populations of cells, those that will develop into the Schwann cells and those that will develop into DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/>Boundary cap neural crest stem cells are some of the transient cells that give rise to the neurons and glia of the DRG.<ref name="PMID24884373"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. The multipotent Sox10+ and Kit-/Kit+ cells usually differentiate into neurons or glias during later stages following migration. <ref name="PMID24273191"/> TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. <ref name="PMID20017208"/> . These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. These transcription factors act as some of the first factors in signaling neurogenesis in the DRG, which marks the beginning of differentiation.<ref name="PMID24004948"/> Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>. Ngn2 leads to the first initiation of neurogenesis. <ref name="PMID20017208"/><br />
<br />
Many receptor kinases also aid in the migration and formation of DRG, specifically ErbB family with erbb2 and erbb3.<ref name="PMID24004948"/><br />
<br />
Neural Crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, lead to the generation of the TrkB and TrkC neurons. The second population, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, leads to the generation of TrkA neurons in this area. <ref name="PMID20017208"/><br />
<br />
==Neuron Development==<br />
The SOX2 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the Dorsal Root Ganglion. <ref name="PMID21549328"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neurons. SOX2 is thought to be bound to the progenitors NGN1 and MASH1 via a promoter region. <ref name="PMID21549328"/><br />
<br />
==Glial Development==<br />
Schwaan cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, schwaan cell precursors are derived from neural crest cells. <br />
Schwaan cells also have the capacity to derive melanocytes through schwaan to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/> <br />
<br />
=Adult Function=<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/><br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes.<br />
<ref name="PMID22052556"/><br />
<br />
=Tissue Structure=<br />
<br />
The Dorsal root ganglion structure is less defined by its shape but by its function. The dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord . They have long axons known as afferents that are long so they can extend from dendrites on the skin to other tissues and organs throughout the body such as muscles,tendons,joints then to the brain. DRG neurons are psuedo-unipolar in shape, is several centimeters long and contains several cell bodies .<br />
<br />
[[File:drg_SKETCH.jpg|400px|thumb|right| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
=Molecular Mechanisms / Factors / Genes=<br />
==Transcription Factors==<br />
===Sry-related HMG box (Sox)===<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. The expression of ErbB3 is regulated by the transcription factor Sox10 and its level is consistently maintained throughout the period of neural crest cell migration <ref name="PMID11156606"/>. Sox10 is also widely expressed in the dorsal root ganglia as well as its surrounding spinal nerves <ref name="PMID9720918"/><br />
<br />
===Rbpj===<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
===Neurogenin===<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are notably expressed during neural crest migration and early dorsal root gangliogenesis. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
===Glial cell-line-derived neurotrophic factor (GDNF)===<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
===Runx===<br />
<ref name="PMID16446142"/>.<br />
<br />
==Signalling pathway==<br />
===ErbB===<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
===Notch signalling===<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/><br />
<br />
=Abnormalities / Abnormal Development=<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg|400px]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
=Animal Models=<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
Since lower back pain and sciatica are becoming more common medical issues, studies has been carried out to display these problems in animals. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This models exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra, to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis. <br />
<br />
As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.<br />
<br />
==Zebrafish Model==<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|left|Neural crest migration and somite development in zebrafish.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||400px|thumb|left|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
=Current Research (Labs)=<br />
<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|400px|thumb|left|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing ( 2012 Sapunar et al). This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." ( 2012 Sapunar et al).<br />
<br />
=Glossary=<br />
<br />
<br />
<br />
<br />
<br />
=Reference List=<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_(CCD).png&diff=354319
File:Dorsal Root Ganglion (CCD).png
2018-09-17T22:22:40Z
<p>Z5229399: </p>
<hr />
<div>==Copyright==<br />
© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2012<br />
<br />
==Reference==<br />
Lin, X.-Y., Yang, J., Li, H.-M., Hu, S.-J., & Xing, J.-L. (2012). Dorsal root ganglion compression as an animal model of sciatica and low back pain. Neuroscience Bulletin, 28(5), 618–630. http://doi.org/10.1007/s12264-012-1276-9</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_(CCD).png&diff=354317
File:Dorsal Root Ganglion (CCD).png
2018-09-17T22:21:53Z
<p>Z5229399: </p>
<hr />
<div>Copyright © Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2012<br />
<br />
Reference<br />
Lin, X.-Y., Yang, J., Li, H.-M., Hu, S.-J., & Xing, J.-L. (2012). Dorsal root ganglion compression as an animal model of sciatica and low back pain. Neuroscience Bulletin, 28(5), 618–630. http://doi.org/10.1007/s12264-012-1276-9</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=354315
2018 Group Project 5
2018-09-17T22:19:50Z
<p>Z5229399: /* Animal Models */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
=Introduction=<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
=History=<br />
=Embryonic Origins=<br />
==Early Development==<br />
In the trunk of the embryo, a small number of neural crest cells (NCCs) migrate ventrally through the dorsal anteriorsclerotome, travelling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination. NCCs undergoes a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>.<br />
<br />
=Developmental Process=<br />
==Neural Crest Migration in Formation of the DRG==<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development through the anterior somite. Depending on where these cells cease their migratio will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites, lateral to the neural tube. <ref name="PMID15590743"/>. Both populations of cells, those that will develop into the Schwann cells and those that will develop into DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/>Boundary cap neural crest stem cells are some of the transient cells that give rise to the neurons and glia of the DRG.<ref name="PMID24884373"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. The multipotent Sox10+ and Kit-/Kit+ cells usually differentiate into neurons or glias during later stages following migration. <ref name="PMID24273191"/> TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. <ref name="PMID20017208"/> . These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. These transcription factors act as some of the first factors in signaling neurogenesis in the DRG, which marks the beginning of differentiation.<ref name="PMID24004948"/> Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>. Ngn2 leads to the first initiation of neurogenesis. <ref name="PMID20017208"/><br />
<br />
Many receptor kinases also aid in the migration and formation of DRG, specifically ErbB family with erbb2 and erbb3.<ref name="PMID24004948"/><br />
<br />
Neural Crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, lead to the generation of the TrkB and TrkC neurons. The second population, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, leads to the generation of TrkA neurons in this area. <ref name="PMID20017208"/><br />
<br />
==Neuron Development==<br />
The SOX2 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the Dorsal Root Ganglion. <ref name="PMID21549328"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neurons. SOX2 is thought to be bound to the progenitors NGN1 and MASH1 via a promoter region. <ref name="PMID21549328"/><br />
<br />
==Glial Development==<br />
Schwaan cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, schwaan cell precursors are derived from neural crest cells. <br />
Schwaan cells also have the capacity to derive melanocytes through schwaan to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/> <br />
<br />
=Adult Function=<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/><br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes.<br />
<ref name="PMID22052556"/><br />
<br />
=Tissue Structure=<br />
<br />
The Dorsal root ganglion structure is less defined by its shape but by its function. The dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord . They have long axons known as afferents that are long so they can extend from dendrites on the skin to other tissues and organs throughout the body such as muscles,tendons,joints then to the brain. DRG neurons are psuedo-unipolar in shape, is several centimeters long and contains several cell bodies .<br />
<br />
[[File:drg_SKETCH.jpg|400px|thumb|right| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
=Molecular Mechanisms / Factors / Genes=<br />
==Transcription Factors==<br />
===Sry-related HMG box (Sox)===<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. The expression of ErbB3 is regulated by the transcription factor Sox10 and its level is consistently maintained throughout the period of neural crest cell migration <ref name="PMID11156606"/>. Sox10 is also widely expressed in the dorsal root ganglia as well as its surrounding spinal nerves <ref name="PMID9720918"/><br />
<br />
===Rbpj===<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
===Neurogenin===<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are notably expressed during neural crest migration and early dorsal root gangliogenesis. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
===Glial cell-line-derived neurotrophic factor (GDNF)===<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
===Runx===<br />
<ref name="PMID16446142"/>.<br />
<br />
==Signalling pathway==<br />
===ErbB===<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
===Notch signalling===<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/><br />
<br />
=Abnormalities / Abnormal Development=<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg|400px]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
=Animal Models=<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).png|400px]]”<br />
<br />
==Zebrafish Model==<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|left|Neural crest migration and somite development in zebrafish.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||400px|thumb|left|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
=Current Research (Labs)=<br />
<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|400px|thumb|left|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing ( 2012 Sapunar et al). This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." ( 2012 Sapunar et al).<br />
<br />
=Glossary=<br />
<br />
<br />
<br />
<br />
<br />
=Reference List=<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=354313
2018 Group Project 5
2018-09-17T22:18:59Z
<p>Z5229399: /* Animal Models */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
=Introduction=<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
=History=<br />
=Embryonic Origins=<br />
==Early Development==<br />
In the trunk of the embryo, a small number of neural crest cells (NCCs) migrate ventrally through the dorsal anteriorsclerotome, travelling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination. NCCs undergoes a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>.<br />
<br />
=Developmental Process=<br />
==Neural Crest Migration in Formation of the DRG==<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development through the anterior somite. Depending on where these cells cease their migratio will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites, lateral to the neural tube. <ref name="PMID15590743"/>. Both populations of cells, those that will develop into the Schwann cells and those that will develop into DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/>Boundary cap neural crest stem cells are some of the transient cells that give rise to the neurons and glia of the DRG.<ref name="PMID24884373"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. The multipotent Sox10+ and Kit-/Kit+ cells usually differentiate into neurons or glias during later stages following migration. <ref name="PMID24273191"/> TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. <ref name="PMID20017208"/> . These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. These transcription factors act as some of the first factors in signaling neurogenesis in the DRG, which marks the beginning of differentiation.<ref name="PMID24004948"/> Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>. Ngn2 leads to the first initiation of neurogenesis. <ref name="PMID20017208"/><br />
<br />
Many receptor kinases also aid in the migration and formation of DRG, specifically ErbB family with erbb2 and erbb3.<ref name="PMID24004948"/><br />
<br />
Neural Crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, lead to the generation of the TrkB and TrkC neurons. The second population, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, leads to the generation of TrkA neurons in this area. <ref name="PMID20017208"/><br />
<br />
==Neuron Development==<br />
The SOX2 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the Dorsal Root Ganglion. <ref name="PMID21549328"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neurons. SOX2 is thought to be bound to the progenitors NGN1 and MASH1 via a promoter region. <ref name="PMID21549328"/><br />
<br />
==Glial Development==<br />
Schwaan cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, schwaan cell precursors are derived from neural crest cells. <br />
Schwaan cells also have the capacity to derive melanocytes through schwaan to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/> <br />
<br />
=Adult Function=<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/><br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes.<br />
<ref name="PMID22052556"/><br />
<br />
=Tissue Structure=<br />
<br />
The Dorsal root ganglion structure is less defined by its shape but by its function. The dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord . They have long axons known as afferents that are long so they can extend from dendrites on the skin to other tissues and organs throughout the body such as muscles,tendons,joints then to the brain. DRG neurons are psuedo-unipolar in shape, is several centimeters long and contains several cell bodies .<br />
<br />
[[File:drg_SKETCH.jpg|400px|thumb|right| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
=Molecular Mechanisms / Factors / Genes=<br />
==Transcription Factors==<br />
===Sry-related HMG box (Sox)===<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. The expression of ErbB3 is regulated by the transcription factor Sox10 and its level is consistently maintained throughout the period of neural crest cell migration <ref name="PMID11156606"/>. Sox10 is also widely expressed in the dorsal root ganglia as well as its surrounding spinal nerves <ref name="PMID9720918"/><br />
<br />
===Rbpj===<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
===Neurogenin===<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are notably expressed during neural crest migration and early dorsal root gangliogenesis. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
===Glial cell-line-derived neurotrophic factor (GDNF)===<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
===Runx===<br />
<ref name="PMID16446142"/>.<br />
<br />
==Signalling pathway==<br />
===ErbB===<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
===Notch signalling===<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/><br />
<br />
=Abnormalities / Abnormal Development=<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg|400px]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
=Animal Models=<br />
<br />
“[[File:Dorsal Root Ganglion (CCD).jpg|400px]]”<br />
<br />
==Zebrafish Model==<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|left|Neural crest migration and somite development in zebrafish.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||400px|thumb|left|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
=Current Research (Labs)=<br />
<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|400px|thumb|left|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing ( 2012 Sapunar et al). This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." ( 2012 Sapunar et al).<br />
<br />
=Glossary=<br />
<br />
<br />
<br />
<br />
<br />
=Reference List=<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=354311
2018 Group Project 5
2018-09-17T22:16:56Z
<p>Z5229399: /* Abnormalities / Abnormal Development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
=Introduction=<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
=History=<br />
=Embryonic Origins=<br />
==Early Development==<br />
In the trunk of the embryo, a small number of neural crest cells (NCCs) migrate ventrally through the dorsal anteriorsclerotome, travelling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination. NCCs undergoes a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube <ref name="PMID28287247"/>. The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway <ref name="PMID19429784"/>.<br />
<br />
=Developmental Process=<br />
==Neural Crest Migration in Formation of the DRG==<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development through the anterior somite. Depending on where these cells cease their migratio will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites, lateral to the neural tube. <ref name="PMID15590743"/>. Both populations of cells, those that will develop into the Schwann cells and those that will develop into DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/>Boundary cap neural crest stem cells are some of the transient cells that give rise to the neurons and glia of the DRG.<ref name="PMID24884373"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. The multipotent Sox10+ and Kit-/Kit+ cells usually differentiate into neurons or glias during later stages following migration. <ref name="PMID24273191"/> TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. <ref name="PMID20017208"/> . These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/><br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. These transcription factors act as some of the first factors in signaling neurogenesis in the DRG, which marks the beginning of differentiation.<ref name="PMID24004948"/> Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>. Ngn2 leads to the first initiation of neurogenesis. <ref name="PMID20017208"/><br />
<br />
Many receptor kinases also aid in the migration and formation of DRG, specifically ErbB family with erbb2 and erbb3.<ref name="PMID24004948"/><br />
<br />
Neural Crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, lead to the generation of the TrkB and TrkC neurons. The second population, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, leads to the generation of TrkA neurons in this area. <ref name="PMID20017208"/><br />
<br />
==Neuron Development==<br />
The SOX2 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the Dorsal Root Ganglion. <ref name="PMID21549328"/> Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neurons. SOX2 is thought to be bound to the progenitors NGN1 and MASH1 via a promoter region. <ref name="PMID21549328"/><br />
<br />
==Glial Development==<br />
Schwaan cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, schwaan cell precursors are derived from neural crest cells. <br />
Schwaan cells also have the capacity to derive melanocytes through schwaan to melanocyte differentiation that can occur to its retained multipotency. <ref name="PMID28242477"/> <br />
<br />
=Adult Function=<br />
The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. Between the cell bodies are layers of satellite glial cells. <ref name="PMID24641192"/><br />
Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes.<br />
<ref name="PMID22052556"/><br />
<br />
=Tissue Structure=<br />
<br />
The Dorsal root ganglion structure is less defined by its shape but by its function. The dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord . They have long axons known as afferents that are long so they can extend from dendrites on the skin to other tissues and organs throughout the body such as muscles,tendons,joints then to the brain. DRG neurons are psuedo-unipolar in shape, is several centimeters long and contains several cell bodies .<br />
<br />
[[File:drg_SKETCH.jpg|400px|thumb|right| Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion]]<br />
<br />
=Molecular Mechanisms / Factors / Genes=<br />
==Transcription Factors==<br />
===Sry-related HMG box (Sox)===<br />
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved <ref name="PMID16927299"/>. The expression of ErbB3 is regulated by the transcription factor Sox10 and its level is consistently maintained throughout the period of neural crest cell migration <ref name="PMID11156606"/>. Sox10 is also widely expressed in the dorsal root ganglia as well as its surrounding spinal nerves <ref name="PMID9720918"/><br />
<br />
===Rbpj===<br />
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation <ref name="PMID21510873"/>.<br />
<br />
===Neurogenin===<br />
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are notably expressed during neural crest migration and early dorsal root gangliogenesis. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development <ref name="PMID10398684"/>.<br />
<br />
===Glial cell-line-derived neurotrophic factor (GDNF)===<br />
GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. <ref name="PMID18629541"/><br />
<br />
===Runx===<br />
<ref name="PMID16446142"/>.<br />
<br />
==Signalling pathway==<br />
===ErbB===<br />
ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells <ref name="PMID19046966"/>. In particular, ErbB3 and its complementary ligand Nrg1 are strongly expressed in neural crest cells and a defect in any components will result in abnormalities in migration of neural crest cells to the mesenchyme lateral of the dorsal aorta <ref name="PMID9637684"/>. <br />
<br />
===Notch signalling===<br />
The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration <ref name="PMID21510873"/><br />
<br />
=Abnormalities / Abnormal Development=<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg|400px]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
=Animal Models=<br />
==Zebrafish Model==<br />
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|left|Neural crest migration and somite development in zebrafish.]]<br />
<br />
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and dorsal root ganglia development<ref name="PMID9006077"/>. It has been demonstrated that the myotome of the zebrafish contributes more in the establishment of neural crest cell migration patterns together with neural crest cells<ref name="PMID1292751"/>. In particular, the adaxial cells, the first cells to develop and migrate from the myotome, helps in the regulation of trunk neural crest migration patterns. These slow muscle precursors have been shown to be crucial for normal migration patterns as their removal resulted in the accumulation of trunk neural crest cells at the level of the notochord<ref name="PMID16162652"/>.<br />
<br />
Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres<ref name="PMID10769242"/>, which was earlier discussed to be important for normal neural crest migration. Shh signalling directs the differentiation of neural crest cells into neurons of the DRG by activating the expression of ngn1 gene, though it does not influence the normal development of early trunk neural crest<ref name="PMID13129844"/>. The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||400px|thumb|left|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
=Current Research (Labs)=<br />
<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
<br />
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ]<br />
<br />
[[File:Microphotograph_of_drg.jpeg|400px|thumb|left|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
The link provided above is a recent research journal that involves an approach in developing a new therapeutic target for neuropathic pain . It is known that during nerve injury or inflammation the dorsal root ganglion neurons have the potential to be a source of increased nocioceptive signalling through increasing neuron excitability and creating ectopic discharges. Therefore ,this provides the opportunity for the anesthesia of DRG neurons to prevent pathological discharges such as ectopic discharges from developing ( 2012 Sapunar et al). This research journal seeks to provide an alternative to the application of therapeutic agents and further explains the importance of DRG as a "targeted therapuetic agent". It was concluded that "Such an approach may provide adequate specificity to capitalize on the new knowledge of peripheral sensory nerve function in painful conditions." ( 2012 Sapunar et al).<br />
<br />
=Glossary=<br />
<br />
<br />
<br />
<br />
<br />
=Reference List=<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}<br />
{{#pmid:24884373|PMID24884373}}<br />
{{#pmid:16162652|PMID16162652}}<br />
{{#pmid:9006077|PMID9006077}}<br />
{{#pmid:1292751|PMID1292751}}<br />
{{#pmid:10769242|PMID10769242}}<br />
{{#pmid:13129844|PMID13129844}}<br />
{{#pmid:3549390|PMID3549390}}<br />
{{#pmid:24004948|PMID24004948}}<br />
{{#pmid:24641192|PMID24641192}}<br />
{{#pmid:22052556|PMID22052556}}<br />
{{#pmid:24273191|PMID24273191}}<br />
{{#pmid:28242477|PMID28242477}}<br />
{{#pmid:19046966|PMID19046966}}<br />
{{#pmid:9637684|PMID9637684}}<br />
{{#pmid:16927299|PMID16927299}}<br />
{{#pmid:11156606|PMID11156606}}<br />
{{#pmid:9720918|PMID9720918}}<br />
{{#pmid:21510873|PMID21510873}}<br />
{{#pmid:18629541|PMID18629541}}<br />
{{#pmid:10398684|PMID10398684}}<br />
{{#pmid:16446142|PMID16446142}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_(CCD).png&diff=354309
File:Dorsal Root Ganglion (CCD).png
2018-09-17T22:16:14Z
<p>Z5229399: </p>
<hr />
<div>Copyright © Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2012</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_(CCD).png&diff=354307
File:Dorsal Root Ganglion (CCD).png
2018-09-17T22:15:36Z
<p>Z5229399: </p>
<hr />
<div></div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=352057
2018 Group Project 5
2018-09-04T01:47:33Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development. Depending on where these cells cease their migration will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites. <ref name="PMID15590743"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>.<br />
<br />
===Neuron Development===<br />
The SOX2 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the Dorsal Root Ganglion.<br />
<br />
===Glial Development===<br />
<br />
==Adult Function==<br />
<br />
==Tissue / Organ Structure==<br />
<br />
==Molecular Mechanisms / Factors / Genes==<br />
<br />
===CXCR4 Chemokine Receptor===<br />
<br />
==Abnormalities / Abnormal Development==<br />
<br />
Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
==Animal Models==<br />
===Zebrafish Model===<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg||400px|thumb|left|Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.]]<br />
<br />
==Current Research (Labs)==<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
[[File:Microphotograph_of_drg.jpeg|400px|thumb|left|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]]<br />
<br />
==Glossary==<br />
<br />
<br />
<br />
<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}<br />
{{#pmid:21549328|PMID21549328}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2018_Group_Project_5&diff=352003
Talk:2018 Group Project 5
2018-09-04T01:30:05Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
{{2018ANAT2341ProjectDiscussion}}<br />
<br />
<!-- Students - Please do not remove the above templates.--><br />
<br />
[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)<br />
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)<br />
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)<br />
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)<br />
<br />
==Introduction==<br />
*A good article for the overview of trunk neural crest cells<br />
<br />
{{#pmid:28287247}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
==Adult Function==<br />
*Differentiation process<br />
*When they start to function<br />
==Tissue / Organ structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"<br />
<br />
{{#pmid:20881125}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)<br />
<br />
==Abnormalities / Abnormal development==<br />
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
==Animal Models==<br />
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"<br />
<br />
{{#pmid:16162652}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)<br />
<br />
<br />
"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."<br />
<br />
Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg]]<br />
<br />
"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."<br />
<br />
{{#pmid:18599505}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)<br />
<br />
<br />
"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."<br />
<br />
{{#pmid:26256768}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)<br />
<br />
==Current research (Labs)==<br />
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)<br />
==Glossary==<br />
*Brief, clear and concise<br />
==Reference==</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_disorder.jpg&diff=351999
File:Dorsal Root Ganglion disorder.jpg
2018-09-04T01:29:37Z
<p>Z5229399: </p>
<hr />
<div>==Legend==<br />
<br />
===Reference===<br />
{{#pmid:24682971}}<br />
<br />
===Copyright===<br />
© 2014 American Academy of Neurology<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
{{Student image 2018}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_disorder.jpg&diff=351771
File:Dorsal Root Ganglion disorder.jpg
2018-08-28T03:04:13Z
<p>Z5229399: /* Copyright */</p>
<hr />
<div>==Legend==<br />
<br />
===Reference===<br />
<br />
====Copyright====<br />
<br />
{{Student image 2018}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_disorder.jpg&diff=351769
File:Dorsal Root Ganglion disorder.jpg
2018-08-28T03:03:52Z
<p>Z5229399: </p>
<hr />
<div>==Legend==<br />
<br />
===Reference===<br />
<br />
====Copyright====<br />
<br />
{{2018 Student image}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2018_Group_Project_5&diff=351767
Talk:2018 Group Project 5
2018-08-28T03:02:25Z
<p>Z5229399: /* Abnormalities / Abnormal development */</p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
{{2018ANAT2341ProjectDiscussion}}<br />
<br />
<!-- Students - Please do not remove the above templates.--><br />
<br />
[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)<br />
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)<br />
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)<br />
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)<br />
<br />
==Introduction==<br />
*A good article for the overview of trunk neural crest cells<br />
<br />
{{#pmid:28287247}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
==Adult Function==<br />
*Differentiation process<br />
*When they start to function<br />
==Tissue / Organ structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"<br />
<br />
{{#pmid:20881125}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)<br />
<br />
==Abnormalities / Abnormal development==<br />
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS<br />
<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
<br />
===Reference===<br />
{{#pmid:24682971}}<br />
<br />
===Copyright===<br />
© 2014 American Academy of Neurology<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
==Animal Models==<br />
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"<br />
<br />
{{#pmid:16162652}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)<br />
<br />
<br />
"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."<br />
<br />
Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg]]<br />
<br />
"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."<br />
<br />
{{#pmid:18599505}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)<br />
<br />
<br />
"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."<br />
<br />
{{#pmid:26256768}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)<br />
<br />
==Current research (Labs)==<br />
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)<br />
==Glossary==<br />
*Brief, clear and concise<br />
==Reference==</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2018_Group_Project_5&diff=351763
Talk:2018 Group Project 5
2018-08-28T02:52:40Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
{{2018ANAT2341ProjectDiscussion}}<br />
<br />
<!-- Students - Please do not remove the above templates.--><br />
<br />
[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)<br />
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)<br />
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)<br />
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)<br />
<br />
==Introduction==<br />
*A good article for the overview of trunk neural crest cells<br />
<br />
{{#pmid:28287247}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
==Adult Function==<br />
*Differentiation process<br />
*When they start to function<br />
==Tissue / Organ structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"<br />
<br />
{{#pmid:20881125}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)<br />
<br />
==Abnormalities / Abnormal development==<br />
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
<br />
===Reference===<br />
{{#pmid:24682971}}<br />
<br />
===Copyright===<br />
© 2014 American Academy of Neurology<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
<br />
<br />
==Animal Models==<br />
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"<br />
<br />
{{#pmid:16162652}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)<br />
<br />
<br />
"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."<br />
<br />
Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg]]<br />
<br />
"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."<br />
<br />
{{#pmid:18599505}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)<br />
<br />
<br />
"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."<br />
<br />
{{#pmid:26256768}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)<br />
<br />
==Current research (Labs)==<br />
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)<br />
==Glossary==<br />
*Brief, clear and concise<br />
==Reference==</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2018_Group_Project_5&diff=351761
Talk:2018 Group Project 5
2018-08-28T02:50:48Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
{{2018ANAT2341ProjectDiscussion}}<br />
<br />
<!-- Students - Please do not remove the above templates.--><br />
<br />
[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)<br />
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)<br />
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)<br />
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)<br />
<br />
==Introduction==<br />
*A good article for the overview of trunk neural crest cells<br />
<br />
{{#pmid:28287247}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
==Adult Function==<br />
*Differentiation process<br />
*When they start to function<br />
==Tissue / Organ structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"<br />
<br />
{{#pmid:20881125}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)<br />
<br />
==Abnormalities / Abnormal development==<br />
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
<br />
Reference<br />
{{#pmid:24682971}}<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
<br />
<br />
==Animal Models==<br />
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"<br />
<br />
{{#pmid:16162652}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)<br />
<br />
<br />
"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."<br />
<br />
Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg]]<br />
<br />
"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."<br />
<br />
{{#pmid:18599505}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)<br />
<br />
<br />
"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."<br />
<br />
{{#pmid:26256768}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)<br />
<br />
==Current research (Labs)==<br />
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)<br />
==Glossary==<br />
*Brief, clear and concise<br />
==Reference==</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2018_Group_Project_5&diff=351701
Talk:2018 Group Project 5
2018-08-27T21:11:10Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
{{2018ANAT2341ProjectDiscussion}}<br />
<br />
<!-- Students - Please do not remove the above templates.--><br />
<br />
[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)<br />
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)<br />
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)<br />
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)<br />
<br />
==Introduction==<br />
*A good article for the overview of trunk neural crest cells<br />
<br />
{{#pmid:28287247}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
==Adult Function==<br />
*Differentiation process<br />
*When they start to function<br />
==Tissue / Organ structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"<br />
<br />
{{#pmid:20881125}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)<br />
<br />
==Abnormalities / Abnormal development==<br />
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
<br />
"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."<br />
<br />
{{#pmid:24682971}}<br />
<br />
==Animal Models==<br />
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"<br />
<br />
{{#pmid:16162652}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)<br />
<br />
<br />
"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."<br />
<br />
Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg]]<br />
<br />
"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."<br />
<br />
{{#pmid:18599505}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)<br />
<br />
<br />
"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."<br />
<br />
{{#pmid:26256768}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)<br />
<br />
==Current research (Labs)==<br />
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)<br />
==Glossary==<br />
*Brief, clear and concise<br />
==Reference==</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=351699
2018 Group Project 5
2018-08-27T21:07:59Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development. Depending on where these cells cease their migration will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites. <ref name="PMID15590743"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>.<br />
<br />
==Adult Function==<br />
==Tissue / Organ Structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
===CXCR4 Chemokine Receptor===<br />
<br />
==Abnormalities / Abnormal Development==<br />
===Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
==Animal Models==<br />
===Zebrafish Model===<br />
<br />
==Current Research (Labs)==<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
<br />
==Glossary==<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}<br />
{{#pmid:24682971|PMID24682971}}</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2018_Group_Project_5&diff=351697
Talk:2018 Group Project 5
2018-08-27T21:07:10Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
{{2018ANAT2341ProjectDiscussion}}<br />
<br />
<!-- Students - Please do not remove the above templates.--><br />
<br />
[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)<br />
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)<br />
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)<br />
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)<br />
<br />
==Introduction==<br />
*A good article for the overview of trunk neural crest cells<br />
<br />
{{#pmid:28287247}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
==Adult Function==<br />
*Differentiation process<br />
*When they start to function<br />
==Tissue / Organ structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"<br />
<br />
{{#pmid:20881125}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)<br />
<br />
==Abnormalities / Abnormal development==<br />
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
<br />
{{#pmid:24682971}}<br />
<br />
==Animal Models==<br />
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"<br />
<br />
{{#pmid:16162652}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)<br />
<br />
<br />
"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."<br />
<br />
Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg]]<br />
<br />
"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."<br />
<br />
{{#pmid:18599505}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)<br />
<br />
<br />
"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."<br />
<br />
{{#pmid:26256768}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)<br />
<br />
==Current research (Labs)==<br />
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)<br />
==Glossary==<br />
*Brief, clear and concise<br />
==Reference==</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=Talk:2018_Group_Project_5&diff=351695
Talk:2018 Group Project 5
2018-08-27T21:05:16Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
{{2018ANAT2341ProjectDiscussion}}<br />
<br />
<!-- Students - Please do not remove the above templates.--><br />
<br />
[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)<br />
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)<br />
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)<br />
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)<br />
<br />
==Introduction==<br />
*A good article for the overview of trunk neural crest cells<br />
<br />
{{#pmid:28287247}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
==Adult Function==<br />
*Differentiation process<br />
*When they start to function<br />
==Tissue / Organ structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"<br />
<br />
{{#pmid:20881125}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)<br />
<br />
==Abnormalities / Abnormal development==<br />
*Environmental factors<br />
*Genetic mutations<br />
*Images of how they look like<br />
“[[File:Dorsal Root Ganglion disorder.jpg]]”<br />
==Animal Models==<br />
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"<br />
<br />
{{#pmid:16162652}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)<br />
<br />
<br />
"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."<br />
<br />
Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)<br />
<br />
[[File:Neural crest cell migration in erbb3b mutants.jpg]]<br />
<br />
"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."<br />
<br />
{{#pmid:18599505}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)<br />
<br />
<br />
"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."<br />
<br />
{{#pmid:26256768}}<br />
<br />
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)<br />
<br />
==Current research (Labs)==<br />
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)<br />
==Glossary==<br />
*Brief, clear and concise<br />
==Reference==</div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Dorsal_Root_Ganglion_disorder.jpg&diff=351693
File:Dorsal Root Ganglion disorder.jpg
2018-08-27T21:02:48Z
<p>Z5229399: </p>
<hr />
<div></div>
Z5229399
https://embryology.med.unsw.edu.au/embryology/index.php?title=2018_Group_Project_5&diff=351691
2018 Group Project 5
2018-08-27T21:01:58Z
<p>Z5229399: </p>
<hr />
<div>{{2018ANAT2341ProjectHeader}}<br />
<!-- Students - Please do not remove the above template.--><br />
<br />
{{Editing Links}}<br />
<br />
=Dorsal Root Ganglion=<br />
<br />
==Introduction==<br />
Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).<br />
<br />
==History==<br />
==Embryonic Origins==<br />
==Developmental Process==<br />
===Neural Crest Migration in Formation of the DRG===<br />
<br />
<br />
Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development. Depending on where these cells cease their migration will determine the structure into which they develop. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites. <ref name="PMID15590743"/>.<br />
<br />
[[File:Mouse NT antibody NF Ki67.jpg|300px|thumb|left|A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.]]<br />
<br />
Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then in glia. TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons following the end of the neural crest migration.<ref name="PMID25205394"/>. The precursors that shape the development of TrkB and TrkC neurons are produced first, followed quickly by the precursors that shape the development of TrkA.<ref name="PMID24668479"/>.<br />
<br />
Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.<ref name="PMID24668479"/>.<br />
<br />
==Adult Function==<br />
==Tissue / Organ Structure==<br />
==Molecular Mechanisms / Factors / Genes==<br />
===CXCR4 Chemokine Receptor===<br />
<br />
==Abnormalities / Abnormal Development==<br />
===Dorsal Root Ganglionopathy is responsible for the sensory impairment<br />
<br />
==Animal Models==<br />
===Zebrafish Model===<br />
<br />
==Current Research (Labs)==<br />
Link on current research for DRG {{#pmid:22375099|PMID22375099}}<br />
<br />
==Glossary==<br />
<br />
==Reference List==<br />
{{#pmid:26988118|PMID26988118}}<br />
{{#pmid:20017208|PMID20017208}}<br />
{{#pmid:28373172|PMID28373172}}<br />
{{#pmid:15590743|PMID15590743}}<br />
{{#pmid:20881125|PMID20881125}}<br />
{{#pmid:22375099|PMID22375099}}<br />
{{#pmid:25205394|PMID25205394}}<br />
{{#pmid:24668479|PMID24668479}}</div>
Z5229399