Difference between revisions of "2018 Group Project 5"

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Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop <ref name="PMID15590743"/>. The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/>  
+
Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. <ref name="PMID21510873"/> Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop. <ref name="PMID15590743"/> The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome <ref name="PMID15590743"/>. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.<ref name="PMID3549390"/>  
  
 
[[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.]]
 
[[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.]]
  
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate <ref name="PMID25363691"/>. After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/>
+
Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate. <ref name="PMID25363691"/> After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. <ref name="PMID20017208"/>
  
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/>. Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/>
+
The morphogen Wnt1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors.<ref name="PMID24668479"/> Without Wnt signalling and b-cantenin activity, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. <ref name="PMID25885041"/>
  
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/>. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/>   
+
Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. <ref name="PMID28287247"/> They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. <ref name="PMID24004948"/>   
  
 
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/>
 
Many tyrosine receptor kinases also aid in the migration and formation of DRG<ref name="PMID24004948"/> Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.<ref name="PMID21510873"/> The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. <ref name="PMID20017208"/> In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. <ref name="PMID20534675"/> As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. <ref name="PMID23701859"/>

Revision as of 22:58, 15 October 2018

Projects 2018: 1 Adrenal Medulla | 3 Melanocytes | 4 Cardiac | 5 Dorsal Root Ganglion


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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 which gives rise to non-neuronal cell types such as smooth muscle cells of the cardiovascular system, melanocytes, connective tissues, craniofacial bones and a majority of the peripheral nervous system which includes the dorsal root ganglion. Located on the dorsal root ,which was first discovered in the 1800s by Charles Bell, is a cluster of neurons known as Dorsal Root Ganglion (DRG) also referred to as the spinal ganglia or posterior root ganglia. They are first order neurons of the sensory pathway which are then activated by a variety of stimuli that transmit sensory messages of pain and touch to the central nervous system. Trunk neural crest cells give rise to DRG and sympathetic ganglia (SG) which form along the anterior-posterior axis of the embryo [1].

There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. [2] The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Through the innervation of target areas and tissues by these neurons, organisms are able to detect and process stimuli in the form of pain, pressure, temperature, muscle movement. [3]

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 it .

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 am process known as vivisection , and concluded that "posterior roots seem to be particularly destined for sensibility, while the anterior roots seem to be especially connected with movement"[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].

Stages of Trunk Neural Crest Development

The induction of the neural crest is the first step of trunk neural crest development. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube [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 [8]. 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]:

  1. A dorsolateral pathway between the ectoderm and the somites
  2. A ventro-lateral pathway between and through the somites
  3. 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]

Developmental Process

Neural Crest Migration in Formation of the Dorsal Root Ganglion

Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5. [10] Depending on where these cells cease their migration within the schlerotome will determine the structure into which they develop. [1] The neural crest cells that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome [1]. Both populations of neural crest cells, those that will develop into the glial cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.[11]

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.

Trunk neural crest cells are multipotent, and usually specific differentiation patterns aren't demonstrated until these cells have begun to migrate. [12] After migration and at the beginning of formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. [13]

The morphogen Wnt1 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, Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10+ activity. Specifically for glial cell populations of the DRG, they are completely dependent on Wnt signalling in order to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly play a role in neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. [15]

Other signaling factors that are often implicated in the differentiation of NRG are the ErbB-2 and ErbB-3 molecules that are members of the ErbB receptor kinase family. [7] They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. [16]

Many tyrosine receptor kinases also aid in the migration and formation of DRG[16] Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG, after ipsilateral migration from the dorsal midline, derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC.[10] The second population of cells, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA. [13] In regards to their sensory roles, TrkA+ neurons generally synapse on visceral afferents in nociception and thermoception, and TrkC+ neurons usually synapse on muscular afferents for proprioception. [17] As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. [18]

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 first into neurons and glia through activity of. They are influenced by the enhancer sox10E1 [7].

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, [19] act as the major classes of neurons that form the DRG following the end of the neural crest migration.[20]. 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.[14]. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates wiht. [19]. In the DRG of mice, between E9.5 and E11.5, neural crest cells have begun to differentiate towards their distinct lineage under either a neuronal or glial lineage. [21]

Axonal Targeting

Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. [19] 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. [22]

Nerve Growth Factors

Nerve Growth Factors(NGF) are important regulators of specific dorsal-lateral axonal growth of the neurons in the DRG. Specifically with TrkA+ neurons, NGF signalling and binding is required in order for the axons of these neurons to meet their targets, and nociception is severely affected due to the lack of communication between the DRG and target tissues. [23] Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments. [24] Without the binding of these factors onto the specific tyrosine receptor kinases of the developing neurons of the DRG during the embryonic period, neurons undergo apoptosis. [25].

Neurotrophin-3

Neurotrophin-3 (NT-3) has been shown to be essential in driving growth towards target tissues in the majority of neurons, but most specifically in proprioceptors of the developing DRG. [26] Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following neural crest migration. Furthermore, reductions in NT-3 has been shown to coincide with a lack of muscle innervation by DRG neurons due to reduced numbers of neurons involved in proprioception [26]. A lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show a reduced DRG cell volume compared to the wild type mice. Deficiencies in neurons begin to appear around E11 and continue through E13. By E13 for mice who are deficient in NT-3, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. [25] As NT-3 is important in driving growth, glial-derived neurotrophic factor(GDNF) has been demonstrated to suppress and restrict growth and branching to balance the activity of NT-3 through its direct down-regulation of the neurotrophin embryonically. [27]

Brn3a and Brn3b

Transcription factors Brn3a and Brn3b are important regulators in how specific neurons of the DRG extend into the spinal cord in order to transmit signals into the the CNS. They are expressed within all differentiating neurons of the DRG during neurogenesis and expression patterns begin to appear around E9.5[28]. Without these factors, the afferents of TrkA+ neurons do not enter into the dorsal horn, and similarly the afferents of TrkC+ neurons do not enter into the ventral horn. These deficiencies lead to disruptions in communication with the spinal cord. Brn3a and Brn3b also directly effect the expression and function of Runx1 and Runx3 signalling, which are also important in specific axonal outgrowth towards targets[28].

Axonal projections in mouse models from neurons in the DRG have been shown to reach the spinal cord on E10.5, and complex signalling further directs these projections to the specific target within the spinal cord through the dorsal and ventral roots. [22]

Neuron Development

In a review in Cell and Tissue Research on the role neurotrophin signalling in the development of the DRG, the authors identified and categorized the developing neurons in the DRG through differences in neuropeptide expression, neurotrophin signalling, receptor concentration on neurons, and ion channel activity and specificity throughout the neurogenesis timeline.[29]

Sox2 and Sox10

The SOX2 and SOX10 transcription factors plays a large role in the individual differentiation of of the neuronal and glial populations within the DRG. Both SOX2 and SOX10 play a regulatory role in the condensing of neurons into the ganglia of the DRG.[30]

SOX10 shows reduced expression in neurons once they have begun down a differentiation path due to down regulation, but it continues to be expressed in glial lineages. [21] SOX10 also can directly affect the expression of Ngn-1. [31] Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron.

Some research has suggested that SOX2 is only involved in glial differention or only involved in neuronal differentiation, but there are many inconsistencies and the final conclusion is unclear. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG.[30]

Tyrosine Receptor Kinases

The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which tyrosine receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling, which guides neurons towards a final sensory fate. [32] 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. [32]

It has been shown in mice models that mice that are NGF of TrkA deficient in vivo will lack the majority of their small diameter neurons involved in nociception following birth. Similarly, mice that are deficient in NT-3 or TrkC are shown to have extremely reduced volumes of mechanoceptive and proprioceptive neurons. [33]

TrkA+ neurons rely on the tyrosine receptor kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. Furthermore, Ret signalling can also promote and maintain the axonal growth of developing mechanoreceptors into the dorsal horn. [17] TrkA+ neurons that do express Ret become nonpeptidergic nociceptive neurons, while TrkA+ neurons that do not express Ret become peptidergic nociceptive neurons. Ret is regulated by the neurotrophic factor NGF and Runx1 signalling.[17] Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. [22]

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 Waves

These waves occur rostral-caudally. These neurogenesis waves represents when each type of sensory neuron begins to develop from precursors following neural crest cell migration and each are structured and moderated by different transcription factors and signalling. High expression of either the neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) transcription factor generally acts as a reliable indicator of which neurogenesis wave is occuring [34]. This timeline represents mouse model of neurogenesis and embryonic developmental days.

E9.5-E11: The first wave of neural crest cell migration into the area of the DRG occurs during this period, which leads to the neurogenesis of neurons expressing high levels of BDNF-specific TrkB receptors and NT-3 specific TrkC receptors. This wave is mostly mediated by Ngn-2. [34]. These neurons will develop into mechanoceptive and proprioceptive neurons [15]. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure[10].

E10.5-13.5: The second wave overlaps with the first wave, and it leads to the neurogenesis of neurons expressing high levels of NGF-specific TrkA receptors, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. [34]. These neurons will develop into nociceptive neurons. [15]. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. [34]

E12-E13: The most rapid proliferation of neurons during the period of neurogenesis. [19].

E12.5-E15.5: A third wave overlaps with the second wave neurogenesis, and even though it mainly gives rise to transient boundary cap neural crest stem cells, it still impacts neurogenesis [35]. These give rise to some nociceptive neurons and later function as the dorsal root entry zone, where sensory neurons from the DRG eventually contact the neural tube. [36]. Depending on whether these cells express Krox20(homologous to Egr2) transcription factor determines their fate. Those cells that continue to express Krox20 will produce peripheral glia, due to the Krox20-mediated activation of myelin genes, while those who stop expressing this protein concentrate in the DRG and increase the population of nociceptive neurons. [15] Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. [37]

E11-E15: Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. [38]

E13.5-E15.5: TrkC+ and TrkA+ neuronal afferents begin to make connection connections in the spinal cord, with the TrkC+ afferents projecting into the ventral horn and TrkA+ projecting into the dorsal horn. [18]

E18.5:Sensory neurons begin to undergo maturation. [28]


Glia Development

Schwann cells are an important glial cell that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Schwann cells also have the capacity to derive melanocytes through Schwann to melanocyte differentiation that can occur due to its retained multipotency. [39]. Satellite cells, which are also important DRG glial cells, remain in the glia.

The Schwann cells and satellite cells usually develop around 1.5 days following the beginning of embryonic neuronal development. [10]. Notch signalling prevents the neural crest cells that are destined to be glial cells from differentiating into neurons, while simultaneously helping to initiate this glial cell differentiation.Notch signalling controls both the size and concentration of the Schwann cells that develop from Schwann cell precursors [40].

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

Neuregulin-1(NRG-1) is also an important molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. [41] NRG-1 and Notch signalling mutually support Schwann cell transitions. Notch signalling increases the receptiveness of Schwann cell precursors to NRG-1 and promotes the NRG-1 signal. NRG-1 binds to both ErbB2 and ErbB3 receptors, and this binding both promotes the growth and survival of Schwann and other glial cells and also plays a role in initiating the glial cell's mylination interactions with the neurons. [42] Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20 activation, since Notch signalling directly opposes myelination onset [40].

Sox10

Even though the SOX10 transcription factor contributes to the differentiation and maturation of neurons into their final expression, SOX10 continues to act as a required factor in neural crest cells differentiating into progenitors and glial cells[10]. The SOX10 transcription factor is expressed in neural crest cells throughout their migration pathway and expression does not cease following this migration, which is a specific quality to glial cells. [41] Even though SOX10 does not affect the survival of neural crest cells, without its expression neural crest cells will not be able to undergo gliogenesis [43]. Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The resarchers observed a smaller DRG in these mice due to this reduced myelination and reduced numbers of Schwann cell precursors. [44]

Timeline of Gliogenesis

This timeline represents mouse model of gliogenesis and embryonic developmental days.

E10.5:Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube [45]

E12-E13:Schwann cell precursors emerge from boundary cap cells. [40] Their proliferation is maintained through NRG-1 activity. [42]

E15-E16:Immature Schwann cells develop from Schwann cell precursors. [40]

E15.5: Krox20(Erg2) is expressed in immature Schwann cells that are destined for myelination. [37]

Adult Function/Tissue structure

The dorsal root ganglion is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. [2] Between the cell bodies are layers of satellite glial cells. [46] It is functional immediately following birth.

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 Dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord ,it is a bulb like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers .These cell bodies are oval in shape they are wrapped completelty in sheaths that may include multiple layers of satellite glial cells (SGCs)[47].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[47].

Furthermore, the DRG has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord.Furthermore, lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root;they are small in diameter and relay pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root,which is responsible for transmitting vibration, touch and pressure information.

Signalling Pathways and Molecular Factors

Signalling pathway

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 [48] 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 [49]. Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR) [50] and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration [51].

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 [52]. As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes [53].

ErbB

ErbB receptors play a role in the development of the dorsal root ganglia. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells [54]. 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 [55].

Notch signalling

The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration [10] This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types [56]

Transcription Factors

Sry-related HMG box (Sox)

Structure of DRG in Sox10-deficient mice

Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved [57]. There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 [58], 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 [59]. 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. [21]

Student created image of the signalling pathway of Sox10

A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions [60], 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 [61]. 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 [62]. 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 [63].

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 expected to inhibit Notch signalling when deleted [10].

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 [34].

Glial cell-line-derived neurotrophic factor (GDNF)

GDNFs belong to a family of ligands that binds to the cell surface alpha receptor GFRalpha1 to induce a signalling cascade pathway for neuron development in the dorsal root ganglia. [64]

Runx

Runx transcription factor signalling plays a role in designating the specific type of neurons present in DRG. The two types of Runx transcription factors, Runx1 and Runx3, works on different cohort of neuronal groups. Runx3, for example, directs the promotion of proprioceptive sensory neurons differentiation by suppressing TrkB expression in prospective TrkC+ sensory neurons [65]

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

Dorsal Root Ganglion disorder.jpg

Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. [66]

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 [67]

Dorsal Root Ganglion (CCD).png

Zebrafish Model

Neural crest migration and somite development in zebrafish.
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 dorsal root ganglia development[68]. 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[69]. 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[70].

Another key aspect in the proper development of dorsal root ganglia (DRG) neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres[71], 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[72]. 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.

Current Research (Labs)


Link on current research for DRG [73]

research on naturopathic pain

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 [73] . 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." [73] .

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 chord stimulation (SCS) which has been successful at providing significant pain relief in patients suffering from chronic neuropathic pain, CRPS and other chronic pain. Although successful and efficient SCS "tends to decay over time in patients with (CRPS)."[74]. 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 [74] 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 .

video on DRG stimulation

DRG patch clamp studies

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"[75] due to a loss of contact with surrounding satellite glial cells. This research lab is studying a new method with less limitations that involves intact DRG neurons through an ex vivo patch clamp procedure which mimicks in vivo conditions through keeping DRG neurons in association with satellite glial cells , secondly this procedure avoids "axonal injury"[75] . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" [75] . Provided below is a link to the research lab and the video on this procedure.

Video DRG patch clamp procedure

Glossary

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

NRH:Neurohgulins

SCS: Spinal Chord Stimulation

SHH: Sonic hedge hog

DRG: Dorsal Root Ganglion

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