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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 big or small to the science of medicine and anatomy that lead up to the dorsal root ganglion being discovered.

1811 -Charles Bell First to Mention that the motor functions of nerve fibers exit via ventral root of the spinal cord, however he did not mention the dorsal root because his discoveries were made through the process of dissecting dead animals(rabbits) which are uncapable of eliciting pain [1] .He found that irritation to anterior columns caused muscle convulsions and irritation to posterior columns were unknown [1]. Bell's mentions in his pamphlet allowed students like Magendie to make further discoveries.

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 [2].

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 (NCC) 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 [3].

In the trunk of the embryo,unipolar neurons from the DRG derive from a small number of neural crest cells (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. NCCs undergo a epithelial-to mesenchymal transition (EMT) once they are induced to become pluripotent, triggering the division from the neural tube [3]. 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 [4].

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 migratio will determine the structure into which they develop[5]. In the mouse model, this migration begins on E8.5[6]. 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 [5]. Both populations of cells, those that will develop into the Schwann cells and those that will develop into DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration.[7] N-cadherin acts an important cell adhesion molecule that directs migration of trunk neural crest cells through specific localization [3].

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.

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. [8] . These progenitor cells specifically reside in the dorsal pole and root. [8]

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.[9] Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA expressing axons, while Ngn1 follows this action with control of both nonmylinated and mylinated axons. Furthermore, the morphogen Wnt1 is also recognized as having an important role in sensory development.[10]. Ngn2 leads to the first initiation of neurogenesis. [8] Another signaling factor that is often implicated in the differentiation of NRG are the ErB molecules. [3]

Many receptor tyrosine kinases also aid in the migration and formation of DRG[9] 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.[6] 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. [8] 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. [11]

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 in glia. They are influenced by the enhancer sox10E1 [3]. The multipotent Sox10+ and Kit-/Kit+ cells usually differentiate into neurons or glias during later stages following migration. [12] TrkA-expressing neurons, nociceptors, and TrkB/TrkC expressing-neurons, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.[13]. 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.[10].

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. [14] 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. [15]

In mice, many neurons have reached their target tissue by embryonic day 13. NT-3 has been shown to be essential in driving this 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 by embryonic day 13, 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. [15]

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. [16] 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. [16]

The tyrosine receptor kinases that are important for neuronal differentiation of the neural crest cells following migration. Depending on which receptor kinase the neuron expresses will affect which neurotrophin factors bind and lead to signalling. [17] 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. [17]

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. [18]

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.[11]

The axons of the developing neurons enter the spinal cord within the dorsal root entry zone. [19]

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. [20]. 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. [6]. 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. Neuregulin-1 is a key neurotrophin that aids this process. [21]

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. [6]. 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. [21] 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. [22]

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 genes,which include either neurogenin-1(Ngn-1) or neurogenin-2 (Ngn-2) [23]. 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. [23]. These neurons will develop into mechanoceptive and proprioceptive neurons [24]. Ngn-2 expression begins to cease around E10.5 [6].

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. [23]. These neurons will develop into nociceptive neurons. [24]

E12.5+: The third wave overlaps with the second wave, and it mainly gives rise to transient boundary cap neural crest stem cells[25]. 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. [26]

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. [27] Between the cell bodies are layers of satellite glial cells. [28] 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. [29]

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. [27] 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. [11]

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

Molecular Mechanisms / Factors / Genes

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 [30]. 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 [21]. Sox10 is also widely expressed in the dorsal root ganglia as well as its surrounding spinal nerves [31]

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 [6].

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 [23].

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. [32]

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 [33]

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 [34]. 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 [35].

Notch signalling

The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration [6] This is done by first creating the neural crest domain within the ectoderm by lateral induction and later lateral induction to differentiate NCC types [36]

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[37]. 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[38]. 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[39].

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[40], 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[41]. 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 [42]

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 [42] . 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." [42] .

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)."[43]. 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 [43] 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"[44] 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"[44] . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells" [44] . Provided below is a link to the research lab and the video on this procedure.

Video DRG patch clamp procedure

Glossary

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:nuerohgulins

SCS: spinal chord stimulation

SHH: sonic hedge hog

Reference List

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