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NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons of the DRG. Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/>
NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons of the DRG. Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. <ref name="PMID8982156"/>


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. 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. <ref name="PMID22326227"/>
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. 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 signalling <ref name="PMID22326227"/>.


===Neuron Development===
===Neuron Development===

Revision as of 13:25, 14 October 2018

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

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Dorsal Root Ganglion

Introduction

Dorsal Root Ganglion is a cluster of neurone found in the dorsal root of the spinal nerve. The cells found in the ganglion develops from the neural crest migration at about 4 weeks post-conception (pc).

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 [1]. However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root[2].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 [3].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"[2].

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 multipotent 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 [4].

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 [4]. 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 [5]. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion [5]. Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites [6]. 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 [4]

There are 3 different pathways that the trunk NCCs can undertake: a dorsolateral pathway between the ectoderm and the somites, a ventro-lateral pathway between and through the somites and a ventro-medial pathway between the neural tube and the posterior sclerotome [6]. 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 [7]

In the trunk of the embryo, unipolar neurons from the DRG comes from a small number of NCCs and migrate ventrally through the dorsal anteriorsclerotome, traveling laterally on the myotomal basal lamina to form the dorsal root ganglia, sympathetic ganglia and adrenal medulla. The differentiation of NCCs is dependent on the instructive cues from their environment when they migrate or when they reach their end destination.

Developmental Process

Neural Crest Migration in Formation of the DRG

Trunk neural crest cells migrate via a ventromedial pathway between the neural tube and dermamyotome during the fourth week of development through the rostral anterior somite. Depending on where these cells cease their migration will determine the structure into which they develop[7]. In the mouse model, this migration begins on E8.5 [8]. The neural crest cells that will divide to form the dorsal root ganglion cease ventral migration once they have reached the area of the perisomitic vessel between the neural tube and the somites, lateral to the neural tube and within the sclerotome [7]. Both populations of 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.[9]

A diagram displaying the developing dorsal root ganglion and ventricular zone in a mouse embryo 12.5 days after fertilization.
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 [10]. 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. [11]

Ngn1 and Ngn2 are transcription factors that shape DRG's role in the sensory system. These transcription factors act as some of the first factors in signaling neurogenesis in the DRG, which marks the beginning of differentiation.[12] Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA expressing axons, while Ngn2 follows this action with control of both non-mylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.[13].

Other signaling factors that is often implicated in the differentiation of NRG are the ErB-2 and ErB-3 molecules that are members of the ErbB receptor kinase family. [4]. They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. [12]

Many receptor tyrosine kinases also aid in the migration and formation of DRG[12] 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 express the neurotrophic receptor kinases TrkB and TrkC.[8] The second population, which proliferate in the peripheral area of the DRG after following either an ipsilateral or contralateral path, leads to neurons expressing the neurotrophin TrkA in this area. [11] In regards to their sensory roles, TrkA-expressing neurons generally synapse on visceral afferent in nociception, and TrkC-expressing neurons usually synapse on muscular afferents for proprioception. [14]

Neuronal and Glial Development and Growth

Progenitor cells act as the beginning catalysts that lead the neural crest cells to differentiate into the neurons and glial cells that will comprise the DRG. Sox10+ progenitors are one of the most common progenitors that plays a role in the differentiation of the neural crest cells first into neurons and then into glia. They are influenced by the enhancer sox10E1 [4]. The multipotent Sox10+ and Kit-/Kit+ cells usually differentiate into neurons or glias during later stages following migration. [15] TrkA-expressing neurons, nociceptors, which are activated by the neurotrophin factor Nerve Growth Factor(NGF), and TrkB/TrkC expressing-neurons, mechanoreceptors and proprioceptors, which are activated by brain-derived neurotrophic factor(BDNF) and neurotrophin-3 (NT-3) respectively, [16] are the three classes of neurons that form the DRG following the end of the neural crest migration.[17]. 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.[13]. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis in the DRG that the neurotrophin is associated with in development. [16]. 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 category. [18]

Axonal Targeting

Nerve Growth Factors(NGF) and are important regulators of specific axonal growth of the neurons in the DRG. Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to receptor tyrosine kinases and promote specific developments. [19] 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. [20]. Axonal projections usually begin at about E10 in mouse embryonic development, but these axons don't reach their targets until E13-E18. [16]

NT-3 has been shown to be essential in driving growth towards target tissues in the majority of neurons of the DRG. Mice that are NT-3 deficient show reduced neuronal survival during DRG development and reduced control over precursor cell differentiation following trunk neural crest migration. In thoracic DRGs, a lack of NT-3 does not prevent migration of NCCs, but mutant mice who are deficient for NT-3 will show both a reduced DRG cell volume compared to the wild type. Deficiencies in neurons begin to appear around embryonic day 11 and continue through embryonic day 13. Initially, between embryonic day 11 and 12, only reductions in precursors can be differentiated between mutants and wild type mice, but by embryonic day 13, there is a clear reduction in the volume of neurons relative to the wild type due to increased apoptosis. [20]

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. 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 signalling [21].

Neuron Development

The SOX2 transcription factor plays a large role in the individual differentiation of of the neuronal and glial populations within the Dorsal Root Ganglion. [22] Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neurons. SOX2 is thought to be bound to the progenitors NGN1 and MASH1 via a promoter region. [22]

The tyrosine receptor kinases are important for neuronal differentiation of the neural crest cells following migration. Depending on which receptor kinase the neuron expresses will effect which neurotrophin factors bind and lead to signalling. [23] The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differntiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA and TrkC neurons. [23]

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. [24]

TrkA neurons rely on the receptor tyrosine kinase Ret, which works in conjunction with GDNF family ligands, during embryonic development for growth and peptidergic quality. 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.[14]

The axons of the developing neurons enter the spinal cord within the dorsal root entry zone. [25]

Timeline of Neurogenesis Waves

These waves occur rostral-caudally. These neurogenesis waves represents when each type of neuron begins to develop following neural crest cell migration and each are structured and moderated by a different neuronal differentiation transcription factors,which include either neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) [26]. This timeline represents mouse 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 BDNF specific TrkB and NT-3 specific TrkC. This wave is mostly mediated by Ngn-2. [26]. These neurons will develop into mechanoceptive and proprioceptive neurons [27]. Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure[8].

E10.5-13.5: The second wave overlaps with the first wave, and it leads to the neurogenesis NGF specific TrkA, satellite glia, and Schwann cells. This wave is mostly mediated by Ngn-1. [26]. These neurons will develop into nociceptive neurons. [27]. Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia [26].

E12-E13: The most rapid proliferation of neurons during the period of neurogenesis. [16].

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[28]. 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. [29]. Depending on whether these cells express Krox20(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. [27] Schwann cell precursors originate from boundary cap cells as do some of the progenitors for nociceptive neurons and satellite glia. [30]

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. [31]

Glial 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 to its retained multipotency. [32]. 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. [8]. 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 [33]. Neuregulin-1 is also an important neurotrophin that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors. [34] 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 erB2 and erB3 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. [35] 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 [33].

Even though the SOX10 transcription factor leads to the differentiation of neurons into their final expression, SOX10 continues to play in differentiated glia and the progenitors, specifically after E9.5. [8]. 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. [34] 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. [36]

Along with SOX10, SOX2 also is an important transcription factor strictly in glial cell differentiation, but not neuronal differentiation. It has been shown that its activity coincides with SOX10 in a similar timeline of activity, but as a more inhibitory factor, and it also is controlled by NOTCH signalling. [37]

Timeline of Gliogenesis

This timeline represents mouse gliogenesis and embryonic developmental days.

E12-E13:Schwann cell precursors emerge from boundary cap cells. [33] Their proliferation is maintained through NRG-1 activity. [35]

E15-E16:Immature Schwann cells develop from schwann cell precursors. [33]

E15.5: Krox20 is expressed in immature Schwann cells. [30]

Adult Function

The dorsal root ganglia is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. [38] Between the cell bodies are layers of satellite glial cells. [39] Specifically for pain sensation, the purinergic receptor P2X3 has been short to be activated in the DRG by ATP. The calcitonin gene related peptide that is expressed in the DRG is similarly involved in inflammatory processes. [40]

A diagram of a cross section of an adult human spinal cord.

There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensations.A and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. [38] The subpopulations of neurons are categorized depending on whether they are nociceptive, mechanoreceptive, or proprioceptive. Each of these afferent neurons has a different target area within the dorsal horn. [14]

Tissue Structure

In humans the Dorsal root ganglion structure is less defined by its shape but by its function. The dorsal root ganglion is a cluster of neurons located in the dorsal root of the spinal cord,it is a bulb like attachment on the dorsal root . It has long axons known as afferents that are capable of extending from dendrites on the skin to other tissues and organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the brain. DRG neurons are psuedo-unipolar in shape, several centimeters long and contain thousands of cell bodies .

Student drawn image of a top view of the spinal cord that shows the location and structure of the dorsal root ganglion

Signalling Pathways and Molecular Factors

Signalling pathway

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 [41]. 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 [42].

Notch signalling

The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration [8] This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types [43]

Transcription Factors

Sry-related HMG box (Sox)

Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved [44]. The expression of ErbB3 is regulated by the transcription factor Sox10 and its level is consistently maintained throughout the period of neural crest cell migration [34]. Sox10 is also widely expressed in the dorsal root ganglia as well as its surrounding spinal nerves [45]

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 [8].

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 [26].

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. [46]

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 [47]

Abnormalities / Abnormal Development

Dorsal Root Ganglionopathy is responsible for the sensory impairment

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."

Animal Models

Dorsal Root Ganglion (CCD).png

Since lower back pain and sciatica are becoming more common medical issues, studies have been carried out to display these problems in animals as animal models. Chronic compression of the dorsal root ganglion (CCD) is one of these models. This model exposes the L4/L5 intervertebral foramin, and stainless steel rods are implanted unilaterally, one rod for each vertebra to chronically compress the lumbar dorsal root ganglion (DRG). Then, CCD can be used to simulate the clinical conditions caused by stenosis, such as a laterally herniated disc or foraminal stenosis.

As the intraforaminal implantation of a rod results in neuronal somal hyperexcitability and spontaneous action potentials associated with hyperalgesia, spontaneous pain, and mechanical allodynia, CCD provides an animal model that mimics radicular pain in humans. This review concerns the mechanisms of neuronal hyperexcitability, focusing on various patterns of spontaneous discharge including one possible pain signal for mechanical allodynia — evoked bursting. Also, new data regarding its significant property of maintaining peripheral input are also discussed. Investigations using this animal model will enhance our understanding of the neural mechanisms for low back pain and sciatica. Furthermore, the peripheral location of the DRG facilitates its use as a locus for controlling pain with minimal central effects, in the hope of ultimately uncovering analgesics that block neuropathic pain without influencing physiological pain.

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[48]. 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[49]. 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[50].

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[51], 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[52]. 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 [53]

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 [53] . 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." [53] .

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)."[54]. 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 [54] 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"[55] 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"[55] . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" [55] . 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

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

Reference List

[56] [11] [57] [7] [58] [53] [17] [13] [59] [22] [28] [50] [48] [49] [51] [52] [9] [12] [39] [40] [15] [32] [41] [42] [26] [44] [34] [45] [8] [46] [26] [47] [38] [4] [5] [43] [8] [14] [25] [34] [36] [23] [19] [24] [20] [29] [27] [8] [26] [10] [31] [33] [30] [16] [6] [37] [35] [12] [21]

  1. van Gijn J. (2011). Charles Bell (1774-1842). J. Neurol. , 258, 1189-90. PMID: 21267589 DOI.
  2. 2.0 2.1 Berkowitz C. (2014). DEFINING A DISCOVERY: PRIORITY AND METHODOLOGICAL CONTROVERSY IN EARLY NINETEENTH-CENTURY ANATOMY. Notes Rec R Soc Lond , 68, 357-72. PMID: 27494015
  3. Tubbs RS, Loukas M, Shoja MM, Shokouhi G & Oakes WJ. (2008). François Magendie (1783-1855) and his contributions to the foundations of neuroscience and neurosurgery. J. Neurosurg. , 108, 1038-42. PMID: 18447728 DOI.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Vega-Lopez GA, Cerrizuela S & Aybar MJ. (2017). Trunk neural crest cells: formation, migration and beyond. Int. J. Dev. Biol. , 61, 5-15. PMID: 28287247 DOI.
  5. 5.0 5.1 5.2 Ahlstrom JD & Erickson CA. (2009). The neural crest epithelial-mesenchymal transition in 4D: a 'tail' of multiple non-obligatory cellular mechanisms. Development , 136, 1801-12. PMID: 19429784 DOI.
  6. 6.0 6.1 6.2 Gammill LS & Roffers-Agarwal J. (2010). Division of labor during trunk neural crest development. Dev. Biol. , 344, 555-65. PMID: 20399766 DOI.
  7. 7.0 7.1 7.2 7.3 Kasemeier-Kulesa JC, Kulesa PM & Lefcort F. (2005). Imaging neural crest cell dynamics during formation of dorsal root ganglia and sympathetic ganglia. Development , 132, 235-45. PMID: 15590743 DOI.
  8. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 Hu ZL, Shi M, Huang Y, Zheng MH, Pei Z, Chen JY, Han H & Ding YQ. (2011). The role of the transcription factor Rbpj in the development of dorsal root ganglia. Neural Dev , 6, 14. PMID: 21510873 DOI.
  9. 9.0 9.1 Teillet MA, Kalcheim C & Le Douarin NM. (1987). Formation of the dorsal root ganglia in the avian embryo: segmental origin and migratory behavior of neural crest progenitor cells. Dev. Biol. , 120, 329-47. PMID: 3549390
  10. 10.0 10.1 Lumb R, Wiszniak S, Kabbara S, Scherer M, Harvey N & Schwarz Q. (2014). Neuropilins define distinct populations of neural crest cells. Neural Dev , 9, 24. PMID: 25363691 DOI.
  11. 11.0 11.1 11.2 George L, Kasemeier-Kulesa J, Nelson BR, Koyano-Nakagawa N & Lefcort F. (2010). Patterned assembly and neurogenesis in the chick dorsal root ganglion. J. Comp. Neurol. , 518, 405-22. PMID: 20017208 DOI.
  12. 12.0 12.1 12.2 12.3 12.4 Malmquist SJ, Abramsson A, McGraw HF, Linbo TH & Raible DW. (2013). Modulation of dorsal root ganglion development by ErbB signaling and the scaffold protein Sorbs3. Development , 140, 3986-96. PMID: 24004948 DOI.
  13. 13.0 13.1 13.2 Marmigère F & Carroll P. (2014). Neurotrophin signalling and transcription programmes interactions in the development of somatosensory neurons. Handb Exp Pharmacol , 220, 329-53. PMID: 24668479 DOI.
  14. 14.0 14.1 14.2 14.3 Honma Y, Kawano M, Kohsaka S & Ogawa M. (2010). Axonal projections of mechanoreceptive dorsal root ganglion neurons depend on Ret. Development , 137, 2319-28. PMID: 20534675 DOI.
  15. 15.0 15.1 Motohashi T, Kitagawa D, Watanabe N, Wakaoka T & Kunisada T. (2014). Neural crest-derived cells sustain their multipotency even after entry into their target tissues. Dev. Dyn. , 243, 368-80. PMID: 24273191 DOI.
  16. 16.0 16.1 16.2 16.3 16.4 Fariñas I, Cano-Jaimez M, Bellmunt E & Soriano M. (2002). Regulation of neurogenesis by neurotrophins in developing spinal sensory ganglia. Brain Res. Bull. , 57, 809-16. PMID: 12031277
  17. 17.0 17.1 Gonsalvez DG, Li-Yuen-Fong M, Cane KN, Stamp LA, Young HM & Anderson CR. (2015). Different neural crest populations exhibit diverse proliferative behaviors. Dev Neurobiol , 75, 287-301. PMID: 25205394 DOI.
  18. Cite error: Invalid <ref> tag; no text was provided for refs named PMID11731238
  19. 19.0 19.1 Coppola V, Kucera J, Palko ME, Martinez-De Velasco J, Lyons WE, Fritzsch B & Tessarollo L. (2001). Dissection of NT3 functions in vivo by gene replacement strategy. Development , 128, 4315-27. PMID: 11684666
  20. 20.0 20.1 20.2 Fariñas I, Yoshida CK, Backus C & Reichardt LF. (1996). Lack of neurotrophin-3 results in death of spinal sensory neurons and premature differentiation of their precursors. Neuron , 17, 1065-78. PMID: 8982156
  21. 21.0 21.1 Zou M, Li S, Klein WH & Xiang M. (2012). Brn3a/Pou4f1 regulates dorsal root ganglion sensory neuron specification and axonal projection into the spinal cord. Dev. Biol. , 364, 114-27. PMID: 22326227 DOI.
  22. 22.0 22.1 22.2 Cimadamore F, Fishwick K, Giusto E, Gnedeva K, Cattarossi G, Miller A, Pluchino S, Brill LM, Bronner-Fraser M & Terskikh AV. (2011). Human ESC-derived neural crest model reveals a key role for SOX2 in sensory neurogenesis. Cell Stem Cell , 8, 538-51. PMID: 21549328 DOI.
  23. 23.0 23.1 23.2 Snider WD & Silos-Santiago I. (1996). Dorsal root ganglion neurons require functional neurotrophin receptors for survival during development. Philos. Trans. R. Soc. Lond., B, Biol. Sci. , 351, 395-403. PMID: 8730777 DOI.
  24. 24.0 24.1 Fariñas I, Wilkinson GA, Backus C, Reichardt LF & Patapoutian A. (1998). Characterization of neurotrophin and Trk receptor functions in developing sensory ganglia: direct NT-3 activation of TrkB neurons in vivo. Neuron , 21, 325-34. PMID: 9728914
  25. 25.0 25.1 Masuda T, Sakuma C, Taniguchi M, Kobayashi K, Kobayashi K, Shiga T & Yaginuma H. (2007). Guidance cues from the embryonic dorsal spinal cord chemoattract dorsal root ganglion axons. Neuroreport , 18, 1645-9. PMID: 17921861 DOI.
  26. 26.0 26.1 26.2 26.3 26.4 26.5 26.6 26.7 Ma Q, Fode C, Guillemot F & Anderson DJ. (1999). Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia. Genes Dev. , 13, 1717-28. PMID: 10398684
  27. 27.0 27.1 27.2 27.3 Gay MH, Valenta T, Herr P, Paratore-Hari L, Basler K & Sommer L. (2015). Distinct adhesion-independent functions of β-catenin control stage-specific sensory neurogenesis and proliferation. BMC Biol. , 13, 24. PMID: 25885041 DOI.
  28. 28.0 28.1 Trolle C, Konig N, Abrahamsson N, Vasylovska S & Kozlova EN. (2014). Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents. BMC Neurosci , 15, 60. PMID: 24884373 DOI.
  29. 29.0 29.1 Golding JP & Cohen J. (1997). Border controls at the mammalian spinal cord: late-surviving neural crest boundary cap cells at dorsal root entry sites may regulate sensory afferent ingrowth and entry zone morphogenesis. Mol. Cell. Neurosci. , 9, 381-96. PMID: 9361276 DOI.
  30. 30.0 30.1 30.2 Maro GS, Vermeren M, Voiculescu O, Melton L, Cohen J, Charnay P & Topilko P. (2004). Neural crest boundary cap cells constitute a source of neuronal and glial cells of the PNS. Nat. Neurosci. , 7, 930-8. PMID: 15322547 DOI.
  31. 31.0 31.1 Wu HH, Bellmunt E, Scheib JL, Venegas V, Burkert C, Reichardt LF, Zhou Z, Fariñas I & Carter BD. (2009). Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat. Neurosci. , 12, 1534-41. PMID: 19915564 DOI.
  32. 32.0 32.1 Petersen J & Adameyko I. (2017). Nerve-associated neural crest: peripheral glial cells generate multiple fates in the body. Curr. Opin. Genet. Dev. , 45, 10-14. PMID: 28242477 DOI.
  33. 33.0 33.1 33.2 33.3 33.4 Woodhoo A, Alonso MB, Droggiti A, Turmaine M, D'Antonio M, Parkinson DB, Wilton DK, Al-Shawi R, Simons P, Shen J, Guillemot F, Radtke F, Meijer D, Feltri ML, Wrabetz L, Mirsky R & Jessen KR. (2009). Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity. Nat. Neurosci. , 12, 839-47. PMID: 19525946 DOI.
  34. 34.0 34.1 34.2 34.3 34.4 Britsch S, Goerich DE, Riethmacher D, Peirano RI, Rossner M, Nave KA, Birchmeier C & Wegner M. (2001). The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. , 15, 66-78. PMID: 11156606
  35. 35.0 35.1 35.2 Fricker FR, Zhu N, Tsantoulas C, Abrahamsen B, Nassar MA, Thakur M, Garratt AN, Birchmeier C, McMahon SB, Wood JN & Bennett DL. (2009). Sensory axon-derived neuregulin-1 is required for axoglial signaling and normal sensory function but not for long-term axon maintenance. J. Neurosci. , 29, 7667-78. PMID: 19535578 DOI.
  36. 36.0 36.1 Peirano RI, Goerich DE, Riethmacher D & Wegner M. (2000). Protein zero gene expression is regulated by the glial transcription factor Sox10. Mol. Cell. Biol. , 20, 3198-209. PMID: 10757804
  37. 37.0 37.1 Wakamatsu Y, Endo Y, Osumi N & Weston JA. (2004). Multiple roles of Sox2, an HMG-box transcription factor in avian neural crest development. Dev. Dyn. , 229, 74-86. PMID: 14699579 DOI.
  38. 38.0 38.1 38.2 Barabas ME, Mattson EC, Aboualizadeh E, Hirschmugl CJ & Stucky CL. (2014). Chemical structure and morphology of dorsal root ganglion neurons from naive and inflamed mice. J. Biol. Chem. , 289, 34241-9. PMID: 25271163 DOI.
  39. 39.0 39.1 Krames ES. (2014). The role of the dorsal root ganglion in the development of neuropathic pain. Pain Med , 15, 1669-85. PMID: 24641192 DOI.
  40. 40.0 40.1 Pan A, Wu H, Li M, Lu D, He X, Yi X, Yan XX & Li Z. (2012). Prenatal expression of purinergic receptor P2X3 in human dorsal root ganglion. Purinergic Signal. , 8, 245-54. PMID: 22052556 DOI.
  41. 41.0 41.1 Birchmeier C. (2009). ErbB receptors and the development of the nervous system. Exp. Cell Res. , 315, 611-8. PMID: 19046966 DOI.
  42. 42.0 42.1 Britsch S, Li L, Kirchhoff S, Theuring F, Brinkmann V, Birchmeier C & Riethmacher D. (1998). The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1, are essential for development of the sympathetic nervous system. Genes Dev. , 12, 1825-36. PMID: 9637684
  43. 43.0 43.1 Cornell RA & Eisen JS. (2005). Notch in the pathway: the roles of Notch signaling in neural crest development. Semin. Cell Dev. Biol. , 16, 663-72. PMID: 16054851 DOI.
  44. 44.0 44.1 Kelsh RN. (2006). Sorting out Sox10 functions in neural crest development. Bioessays , 28, 788-98. PMID: 16927299 DOI.
  45. 45.0 45.1 Bondurand N, Kobetz A, Pingault V, Lemort N, Encha-Razavi F, Couly G, Goerich DE, Wegner M, Abitbol M & Goossens M. (1998). Expression of the SOX10 gene during human development. FEBS Lett. , 432, 168-72. PMID: 9720918
  46. 46.0 46.1 Ernsberger U. (2008). The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons. Cell Tissue Res. , 333, 353-71. PMID: 18629541 DOI.
  47. 47.0 47.1 Kramer I, Sigrist M, de Nooij JC, Taniuchi I, Jessell TM & Arber S. (2006). A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification. Neuron , 49, 379-93. PMID: 16446142 DOI.
  48. 48.0 48.1 Morin-Kensicki EM & Eisen JS. (1997). Sclerotome development and peripheral nervous system segmentation in embryonic zebrafish. Development , 124, 159-67. PMID: 9006077
  49. 49.0 49.1 Raible DW, Wood A, Hodsdon W, Henion PD, Weston JA & Eisen JS. (1992). Segregation and early dispersal of neural crest cells in the embryonic zebrafish. Dev. Dyn. , 195, 29-42. PMID: 1292751 DOI.
  50. 50.0 50.1 Honjo Y & Eisen JS. (2005). Slow muscle regulates the pattern of trunk neural crest migration in zebrafish. Development , 132, 4461-70. PMID: 16162652 DOI.
  51. 51.0 51.1 Barresi MJ, Stickney HL & Devoto SH. (2000). The zebrafish slow-muscle-omitted gene product is required for Hedgehog signal transduction and the development of slow muscle identity. Development , 127, 2189-99. PMID: 10769242
  52. 52.0 52.1 Ungos JM, Karlstrom RO & Raible DW. (2003). Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Development , 130, 5351-62. PMID: 13129844 DOI.
  53. 53.0 53.1 53.2 53.3 Sapunar D, Kostic S, Banozic A & Puljak L. (2012). Dorsal root ganglion - a potential new therapeutic target for neuropathic pain. J Pain Res , 5, 31-8. PMID: 22375099 DOI.
  54. 54.0 54.1 Yang A & Hunter CW. (2017). Dorsal Root Ganglion Stimulation as a Salvage Treatment for Complex Regional Pain Syndrome Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series. Neuromodulation , 20, 703-707. PMID: 28621025 DOI.
  55. 55.0 55.1 55.2 Gong K, Ohara PT & Jasmin L. (2016). Patch Clamp Recordings on Intact Dorsal Root Ganglia from Adult Rats. J Vis Exp , , . PMID: 27768031 DOI.
  56. George L, Dunkel H, Hunnicutt BJ, Filla M, Little C, Lansford R & Lefcort F. (2016). In vivo time-lapse imaging reveals extensive neural crest and endothelial cell interactions during neural crest migration and formation of the dorsal root and sympathetic ganglia. Dev. Biol. , 413, 70-85. PMID: 26988118 DOI.
  57. Ogawa R, Fujita K & Ito K. (2017). Mouse embryonic dorsal root ganglia contain pluripotent stem cells that show features similar to embryonic stem cells and induced pluripotent stem cells. Biol Open , 6, 602-618. PMID: 28373172 DOI.
  58. Kasemeier-Kulesa JC, McLennan R, Romine MH, Kulesa PM & Lefcort F. (2010). CXCR4 controls ventral migration of sympathetic precursor cells. J. Neurosci. , 30, 13078-88. PMID: 20881125 DOI.
  59. Szmulewicz DJ, McLean CA, Rodriguez ML, Chancellor AM, Mossman S, Lamont D, Roberts L, Storey E & Halmagyi GM. (2014). Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS. Neurology , 82, 1410-5. PMID: 24682971 DOI.