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{{ | =Dorsal Root Ganglion= | ||
==Introduction== | |||
[[File:Dorsal Root Ganglia Adult.jpg|450px|thumb|wrap|A diagram of a cross section of an adult human spinal cord.]] | |||
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}}. | |||
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{{#pmid:25271163|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"/>. | |||
<html5media width="480" height="358">https://www.youtube.com/embedv=2dgzEYlq_jU</html5media> | |||
==History== | |||
[[File:François Magendie.jpg|thumb|embed|100px|François Magendie]] | |||
---- | |||
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. | |||
'''''1811 -Charles Bell''''' [[File:CharlesBell001.jpg|thumb|100px|embed|Charles Bell]] | |||
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" | |||
.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. | |||
---- | |||
'''''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, 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}}. | |||
[[File:Johannes Mueller.jpg|thumb|100px|right|Johannes Peter Müller]] | |||
---- | |||
'''''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. | |||
==Embryonic Origins== | |||
[[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]] | |||
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"/>. | |||
===Trunk Neural Crest=== | |||
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"/>. | |||
There are 3 different pathways that the trunk NCCs can undertake <ref name="PMID20399766"/>: | |||
#A dorsolateral pathway between the ectoderm and the somites | |||
#A ventro-lateral pathway between and through the somites | |||
#A ventro-medial pathway between the neural tube and the posterior sclerotome | |||
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"/>. | |||
= | ===Embryonic Function=== | ||
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"/> | |||
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. | |||
= | ==Developmental Process== | ||
= | ===Neural Crest Migration in Formation of the Dorsal Root Ganglion=== | ||
= | |||
==Neural Crest Migration in Formation of the | |||
Trunk | 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"/> | ||
[[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.]] | |||
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"/> | |||
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"/> | |||
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"/> | |||
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"/> | |||
==Neuronal and Glial Development and Growth== | |||
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"/>. | |||
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 neuronal apoptosis <ref name="PMID8208292"/>. | |||
<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 | |||
'''[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. | |||
''</small> | |||
===Axonal Targeting=== | |||
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"/> | |||
====Nerve Growth Factors==== | |||
'''[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"/> | |||
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"/>. | |||
====Neurotrophin-3==== | |||
'''[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"/> | |||
====Brn3a and Brn3b==== | |||
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 | |||
'''[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"/>. | |||
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"/> | |||
===Neuron Development=== | |||
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"/> | |||
====Sox2 and Sox10==== | |||
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"/> | |||
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"/> | |||
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"/> | |||
====Tyrosine Receptor Kinases==== | |||
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"/> | |||
It has been shown in mouse 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"/> | |||
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"/> | |||
[[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. ]] | |||
===Timeline of Neurogenesis=== | |||
Neurogenesis occurs in a 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> | |||
---- | |||
'''E9.5-E11 (Human: Day 22-30):''' The first wave of neurogenesis 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"/>. | |||
---- | |||
'''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"/> | |||
---- | |||
'''E12-E13 (Human: Day 36-42):''' The most rapid proliferation of neurons occurs during this period of neurogenesis. <ref name="PMID9728914"/> | |||
---- | |||
'''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"/> | |||
---- | |||
'''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"/> | |||
---- | |||
'''E18.5+ (Human: Day 60+): ''' Sensory neurons undergo maturation and concentration levels stabilize. <ref name="PMID22326227"/> | |||
===Glia Development=== | |||
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"/> | |||
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"/>. | |||
[[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. | |||
(A) The migration of NCCs from the dorsal neural tube | |||
(B) The migration of NCCs along the ventral path to populate the developing DRG and peripheral nerves | |||
(C) The association of Schwann cell precursors with developing axons | |||
(D) The maturation of Schwann cell precursors into immature Schwann | |||
(E) The differentiation of immature Schwann cells into into myelinating and non-myelinating Schwann cells. | |||
Abbreviations: bc, boundary cap; dr, dorsal root; drg, dorsal root ganglia; nt, neural tube; sn, spinal nerve; vr, ventral root.]] | |||
====NRG-1==== | |||
'''[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"/>. | |||
====Sox10==== | |||
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 number of Schwann cell precursors. <ref name="PMID10757804"/> | |||
====Krox20==== | |||
'''[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"/> | |||
===Timeline of Gliogenesis=== | |||
This timeline represents the 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>. | |||
---- | |||
'''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"/> | |||
---- | |||
'''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"/> | |||
---- | |||
'''E14-E15 (Human: Day 48-54):''' Schwann cell precursors engage with developing axons of the DRG. <ref name="PMID27058953"/> | |||
---- | |||
'''E15-E16 (Human: Day 54-58):''' Immature Schwann cells develop from Schwann cell precursors. <ref name="PMID19525946"/> | |||
---- | |||
'''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"/> | |||
---- | |||
'''E18.5+ (Human: Day 60+):''' Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. <ref name="PMID27058953"/> | |||
---- | |||
==Adult Function/Tissue structure== | |||
The DRG is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. 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.{{#pmid:25271163|PMID25271163}} | |||
[[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]] | |||
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}}. | |||
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. | |||
==Signalling Pathways and Molecular Mechanisms== | |||
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: | |||
===Signalling pathways=== | |||
===='''Wnt'''==== | |||
[[File:Canonical Wnt pathway.jpg|right|300px|thumb|wrap|Overview of the canonical Wnt pathway]] | |||
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"/>. | |||
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"/>. | |||
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"/>. | |||
===='''ErbB'''==== | |||
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"/>. | |||
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"/>. | |||
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"/>. | |||
===='''Notch signalling'''==== | |||
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. | |||
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"/>. | |||
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 "/>. | |||
===Transcription Factors=== | |||
===='''Sry-related HMG box (Sox)'''==== | |||
[[File:Illustration of Sox signalling pathway.jpg|right|300px|thumb|wrap|Student created image of the signalling pathway of Sox10]] | |||
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"/>. | |||
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"/>. | |||
===='''Neurogenin'''==== | |||
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"/>. | |||
===='''Runx'''==== | |||
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"/>. | |||
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"/>. | |||
===='''Rbpj'''==== | |||
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"/>. | |||
==Disorders== | |||
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 | |||
===Sensory Ganglionitis=== | |||
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. | |||
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}} | |||
= | ===Sjögren Syndrome=== | ||
[[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". ]] | |||
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. | |||
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}} | |||
== | ==Animal Models== | ||
= | ===Rat Model=== | ||
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}} | |||
Dorsal Root | “[[File:Dorsal Root Ganglion (CCD).png|400px]]” | ||
===Zebrafish Model=== | |||
[[File:Neural crest migration and somite development in zebrafish.jpeg||400px|thumb|wrap|Neural crest migration and somite development in zebrafish.]] | |||
[[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.]] | |||
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"/>. | |||
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. | |||
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"/>. | |||
==Current Research (Labs)== | |||
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media> | |||
Link on current research for DRG {{#pmid:22375099|PMID22375099}} | '''Link on current research for DRG''' {{#pmid:22375099|PMID22375099}} | ||
[https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ] | [https://www.ncbi.nlm.nih.gov/pubmed/22375099 research on naturopathic pain ] | ||
[[File:Microphotograph_of_drg.jpeg| | [[File:Microphotograph_of_drg.jpeg|300px|thumb|wrap|Microphotograph of dorsal root ganglion from a frozen section including DRG neurons and satellite cells.]] | ||
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}} | |||
. 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}} | |||
. | |||
'''Dorsal root ganglion stimulation''' | |||
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. | |||
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 . | |||
[https://www.youtube.com/watch?v=oTUZBukXRLA video on DRG stimulation] | |||
'''DRG patch clamp studies''' | |||
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media> | |||
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. | |||
[https://www.jove.com/video/54287/patch-clamp-recordings-on-intact-dorsal-root-ganglia-from-adult-rats Video DRG patch clamp procedure] | |||
==Glossary== | |||
'''Dorsalateral''' - related to the back and side | |||
'''Dorsa aorta''' - paired embryological vessels which progress to form the descending aorta | |||
'''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 | |||
'''Neural crest cells''' - a group of cells arising from the ectoderm that differentiates into various cell lineages during the development of the embryo | |||
'''Schwann cells''' - a glial cell in the peripheral nervous system that wraps around the nerve fiber to forms the myelin sheaths | |||
'''ventro-lateral''' - related to the front and side | |||
'''ventro-medial''' - related to the front and to the middle | |||
==List of Abbreviations== | |||
'''AP''': Anterior-posterior | |||
'''BDNF''': Brain-derived neurotrophic factor | |||
'''BMP''': Bone Morphogenetic Protein | |||
'''CCD''': Chronic Compression of DRG | |||
'''CRPS''': Complex Regional Pain Syndrome | |||
'''EGF''': Epidermal Growth Factor | |||
'''EMT''': Epithelial to Mesencyhmal Transition | |||
'''NGF''': Nerve growth factor | |||
'''NGN''': Neurogenin | |||
'''NRG''': Neuregulin | |||
'''NRH''': Neurohgulins | |||
'''NT''': Neurotrophin | |||
'''SCS''': Spinal Chord Stimulation | |||
'''SHH''': Sonic hedgehog | |||
'''DRG''': Dorsal Root Ganglion | |||
'''TRK''': Tyrosine Receptor Kinase | |||
=Reference List= | ==Reference List== | ||
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Latest revision as of 12:31, 15 April 2019
Projects 2018: 1 Adrenal Medulla | 3 Melanocytes | 4 Cardiac | 5 Dorsal Root Ganglion |
Project Pages are currently being updated (notice removed when completed)
Dorsal Root Ganglion
Introduction
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[1].
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[2]. 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[3].
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History
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.
1811 -Charles Bell
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 [4]. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root[5].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" .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.
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 [6].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"[5].
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.
Embryonic Origins
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 [7].
Trunk Neural Crest
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 [7]. 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 [8]. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites [9]. 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 [7].
There are 3 different pathways that the trunk NCCs can undertake [9]:
- A dorsolateral pathway between the ectoderm and the somites
- A ventro-lateral pathway between and through the somites
- A ventro-medial pathway between the neural tube and the posterior sclerotome
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 [1].
Embryonic Function
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. [10]
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.
Developmental Process
Neural Crest Migration in Formation of the Dorsal Root Ganglion
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. [11] 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 [1]. 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.[12]
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. [13]
The protein Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.[14] 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. [15]
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). [16] They are important in regulating and maintaining levels of DRG progenitors and in guiding the migratory peripheral paths of glial cells. [17]
Many tyrosine receptor kinases also aid in the migration and formation of the DRG[17] 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.[11] 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. [13] 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. [18] 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. [19]
Neuronal and Glial Development and Growth
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. [20].
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, [21] act as the major classes of neurons that populate the DRG following the end of the neural crest migration.[22]. 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 neuronal apoptosis [23].
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 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.
Axonal Targeting
Axonal projections of developing neurons begin to reach their target tissues between E12.5-E16.5 in the mouse model[18] 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.[24] 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. [25]
Nerve Growth Factors
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. [26] Along with NGFs in mammals, neurotrophins-3 and 4/5 also bind to tyrosine receptor kinases. [27]
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. [28].
Neurotrophin-3
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. [29] 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 [29]. 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. [28] As NT-3 is important in driving growth,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.[30]
Brn3a and Brn3b
Transcription factors Brn3a and 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 [31]. 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 Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets[31].
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. [32]
Neuron Development
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. [21]
Sox2 and Sox10
The SOX2 and 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.[33] Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. [34]
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. [35] SOX10 also can directly affect the expression of Ngn-1, which is a major transcription factor involved in neurogenesis. [36]
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[33] 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. [37]
Tyrosine Receptor Kinases
The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration.[21]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. [21] 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. 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. [38]
It has been shown in mouse 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. [21]
TrkA+ neurons rely on the receptor tyrosine kinase 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. [18] TrkA+ neurons that express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. [39] Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.[18] Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. [25]
![](/embryology/images/thumb/3/3c/Ngn1_and_Ngn2_in_DRG_development.png/300px-Ngn1_and_Ngn2_in_DRG_development.png)
Timeline of Neurogenesis
Neurogenesis occurs in a 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 neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is in effect. [40]. 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 reference [41]
E9.5-E11 (Human: Day 22-30): The first wave of neurogenesis 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. [40]. These neurons will generally develop into the mechanoceptors and proprioceptors of the DRG [15]. Ngn-2 expression ends around E10.5, but it overlaps slightly with the period of neuronal condensation into ganglion[11].
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. [40]. These neurons will generally develop into the nociceptors of the DRG. [15]. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and it is only expressed following migration and neuronal condensation into ganglion. [40]
E12-E13 (Human: Day 36-42): The most rapid proliferation of neurons occurs during this period of neurogenesis. [21]
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. [42]
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. [19]
E18.5+ (Human: Day 60+): Sensory neurons undergo maturation and concentration levels stabilize. [31]
Glia Development
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. [43] 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.[42]
The Schwann cell precursors and satellite cell precursors usually are derived from neural crest cells about 1.5 days following the beginning of neurogenesis. [11]. 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 [44].
![](/embryology/images/thumb/2/20/Neurogenesis_and_Gliogenesis_Timeline.jpg/450px-Neurogenesis_and_Gliogenesis_Timeline.jpg)
NRG-1
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. [45] 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 helps initiate myelination interactions of the glial cells with peripheral neurons. [46] 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 [44].
Sox10
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[11]. 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. [45] 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 number of Schwann cell precursors. [47]
Krox20
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. [48] Cells that do not express Krox20 concentrate in the DRG and increase the population of nociceptive neurons and non-myelinating glia. [15]
Timeline of Gliogenesis
This timeline represents the mouse model of gliogenesis and embryonic developmental days, and these days were converted into the relative human embryonic development days as a reference [49].
E10.5 (Human: Day 28): Migration of neural crest cells that will differentiate into glial cells of the DRG begins from the neural tube [50]
E12-E13 (Human: Day 36-42): Satellite glial cell precursors begin to differentiate from neural crest cells. [43] Schwann cell precursors emerge from boundary cap neural crest cells that surround the dorsal root entry zone, as well as additional satellite cell precursors [44] Their proliferation is maintained through NRG-1 activity. [46]
E14-E15 (Human: Day 48-54): Schwann cell precursors engage with developing axons of the DRG. [43]
E15-E16 (Human: Day 54-58): Immature Schwann cells develop from Schwann cell precursors. [44]
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. [51]
E18.5+ (Human: Day 60+): Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. [43]
Adult Function/Tissue structure
The DRG is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. 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.[2]
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)[52]. 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[52].
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.
Signalling Pathways and Molecular Mechanisms
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:
Signalling pathways
Wnt
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species [53] 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 [54]. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) [55] and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration [56].
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 [57]. 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 [58].
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 [59].
ErbB
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 [60]. 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 [61].
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 [62].
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 [63], expansion and migration of Schwann cell precursor [64] and providing signals for myelination [65]. 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 [64].
Notch signalling
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 [66]. The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration [11]. This is done through the process of lateral inhibition and lateral induction.
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 [67]. 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 [67]. 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 [68].
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 [69]. 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 [66].
Transcription Factors
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved [70]. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 [71], 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 [72]. 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 [35].
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions [73], 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 [74]. 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 [75]. 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 [76].
Neurogenin
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 [40]. 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 [14].
Runx
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 [77]. 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 [78].
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 [79]. Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons [25] and in the survival and development of DRG neurons [80]. Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons [81].
Rbpj
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 [11].
Disorders
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
Sensory Ganglionitis
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.
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. [82]
Sjögren Syndrome
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.
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. [82]
Animal Models
Rat Model
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 [83]
Zebrafish Model
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[84]. 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[85]. 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[86].
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 [87], 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 [88]. 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.
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 [89]. 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 [90].
Current Research (Labs)
<html5media width="480" height="358">https://www.youtube.com/embed/v=iiqMqXHnAZE</html5media>
Link on current research for DRG [91]
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 [91] . 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." [91] .
Dorsal root ganglion stimulation
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)."[92]. 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.
The research DRG Stimulation as a Salvage Treatment for CRPS Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series [92] 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 .
DRG patch clamp studies
<html5media width="480" height="358">https://www.youtube.com/embed/v=nIAyczCZBYc</html5media>
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"[93] 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"[93] . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" [93] . Provided below is a link to the research lab and the video on this procedure.
Video DRG patch clamp procedure
Glossary
Dorsalateral - related to the back and side
Dorsa aorta - paired embryological vessels which progress to form the descending aorta
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
Neural crest cells - a group of cells arising from the ectoderm that differentiates into various cell lineages during the development of the embryo
Schwann cells - a glial cell in the peripheral nervous system that wraps around the nerve fiber to forms the myelin sheaths
ventro-lateral - related to the front and side
ventro-medial - related to the front and to the middle
List of Abbreviations
AP: Anterior-posterior
BDNF: Brain-derived neurotrophic factor
BMP: Bone Morphogenetic Protein
CCD: Chronic Compression of DRG
CRPS: Complex Regional Pain Syndrome
EGF: Epidermal Growth Factor
EMT: Epithelial to Mesencyhmal Transition
NGF: Nerve growth factor
NGN: Neurogenin
NRG: Neuregulin
NRH: Neurohgulins
NT: Neurotrophin
SCS: Spinal Chord Stimulation
SHH: Sonic hedgehog
DRG: Dorsal Root Ganglion
TRK: Tyrosine Receptor Kinase
Reference List
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