2018 Group Project 5
|Projects 2018: 1 Adrenal Medulla | 3 Melanocytes | 4 Cardiac | 5 Dorsal Root Ganglion|
Dorsal Root Ganglion
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.
There are a few different subpopulations of DRG neurons, and each population plays a specific role in different types of sensory perceptions. A, B, and C nerve fibers show both different sizes of myelination and soma size that correspond to the role they play in the PNS. The cell bodies of all of these neurons are housed in the dorsal root ganglion, and due to their pseudounipolar orientation, can send axons towards their target tissues and the spinal cord. 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.
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 . However, since his experiments were done on dead unconscious animals he was unable to detect the sensory activities of the posterior root.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 .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".
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.
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 .
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 . The EMT process, which generates neural crest cells from the neuroepithelium of the dorsal neural tube, is believed to be enhanced by bone morphogenetic protein (BMP) activation and the promotion of the Wnt Signalling pathway. Once EMT is triggered, the NCCs becomes migratory, leaving the neural tube in a rostral to caudal fashion . Tissues surrounding the trunk NCCs serve as cues to guide their migration, prominently by the somites . 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 .
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
- 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 .
Most of the research into the embryonic development of the DRG analyzes patterning and differentiation of structures, but not embryonic functionality. One method of measuring the functionality of the DRG is through stimulation of the neurons associated with the DRG and observing reflexive responses to stimuli. By E15.5 in rat embryonic development, electrical stimulation of the dorsal root ganglion can produce a depolarizing signal in the ventral root of the spinal cord. Furthermore, reflex discharge patterns from DRG stimulation of a human fetus in the third trimester of development was similar to that of the pattern of a 3-4 day old mammal. The monosynaptic discharge reflex, which involves transmission of a sensory signal through the DRG, can be demonstrated during the late fetal period of most mammals and after birth. Specifically for rats, this reflex could be demonstrated in a basic form by E17.5. 
Neural Crest Migration in Formation of the Dorsal Root Ganglion
Trunk NCCs migrate via a ventro-medial pathway between the neural tube and dermomyotome in a segmented design during the fourth week of development. In the mouse model, this migration begins on E8.5.  The NCCs that will condense to form the DRG cease ventral migration once they have reached the intersomitic area lateral to the neural tube and within the sclerotome . Both populations of NCCs, those that will develop into the glia cells and those that will develop into the neurons of the DRG, follow the same migratory pattern and both precursor cells undergo significant cell death following the migration and before full maturation.
After migration of the trunk NCCs and at the beginning of DRG formation, the DRG only is made up of a core section, which is covered by undifferentiated progenitor cells. These progenitor cells specifically reside in the dorsal pole and root. 
The morphogen Wnt-1 is recognized as having an important signalling role in early sensory development and shaping the migration of precursors. Without Wnt signalling and b-cantenin activity,the neurogenin transciption factor Ngn-2 fails to be expressed properly and Ngn-1 to a lesser degree, which disrupts neurogenesis waves and Sox10 activity. Specifically for glial cell populations of the DRG, Wnt-signalling is necessary in order for these populations to develop distinct lineages during gliogenesis. Even though b-cantenin does not directly control neuronal differentiation and formation, it plays a major role in the progress of the neurogenesis waves that lead to this formation. 
Other signaling factors that are often implicated in the differentiation of DRG are the ErbB2 and ErbB3 molecules that are members of the ErbB receptor kinase family and which interact with neuregulin 1 and 2.  They are important in regards to the control of DRG progenitors and in the migratory paths of mylinating peripheral glial cells. 
Many tyrosine receptor kinases also aid in the migration and formation of DRG Neural crest cells, once they reach the area of DRG propagation, display two different migration patterns in the formation. The cells that proliferate in the core of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinases TrkB and TrkC. The second population of cells, which proliferate in the peripheral area of the DRG derive neurons that preferentially express the neurotrophic tyrosine receptor kinase TrkA.  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.  As important as the signalling through tyrosine receptor kinases are during development, the expression of these receptors decreases significantly following neurogenesis and differentiation. 
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. .
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,  act as the major classes of neurons that form the DRG following the end of the neural crest migration.. The precursors that shape the development of TrkB+ and TrkC+ neurons are produced first, followed quickly by the precursors that shape the development of TrkA+ neurons. Deficiencies in levels of any of the neurotrophins can lead to significant reductions in the the amount of neurons or significant apoptosis of the neurons in the DRG that the neurotrophin associates with. . 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. 
Note: Some of the terms in this section that are important proteins, transcription factors, or molecules in neuronal and glial development and growth in the DRG have been bolded and hyperlinked to Online Mendelian Inheritance in Man, an online catalog of human genes and genetic disorders, in order to provide more information about the factor in question if necessary.
Axonal projections of newly developed neurons in neurogenesis reach their targets between E12.5-E16.5 in the mouse model The axons of neurons in the DRG project to both their target tissues and an area of the spinal cord to transmit sensory signals into the CNS. 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. 
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.  Along with NGFs in mammals, neurotrophins 3 and 4/5 also bind to tyrosine receptor kinases and promote specific developments.  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. .
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.  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 . 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.  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. 
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. 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.
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. 
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.
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. Their expression patterns appear to overlap, so it is deduced that they work congruently in differentiation patterns. 
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.  SOX10 also can directly affect the expression of Ngn-1.  Due to its role in differentiation, alterations to transcriptional levels can prevent the natural neurogenesis of DRG neuron.
SOX2 is required for neurogenesis, and deficiencies in SOX2 activity prevented neural crest cells from differentiating into neuronal, and to a less significant degree glial, lineages. It initially is suppressed in order that EMT can occur and neural crest cells can begin migration, but SOX2 is expressed again once these neural crest cells reach their target migratory area of the DRG and supports specification of these cells. In glial cell lineages, SOX2 prevents immature Schwann cells from developing myelinating properties, and this gene inhibition prevents termination differentiation and indirectly leads to more responsive proliferation. 
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.  The neurons that express high affinity TrkA receptors differentiate into neurons with smaller somas and diameters, while the neurons that express high affinity TrkC receptors differentiate into neurons with larger somas and diameters relatively. Neurons that express high affinity TrkB receptors usually differentiate intermediately between the soma and diameter sizes of TrkA+ and TrkC+ neurons.Developing neurons show specific mRNA expression patterns for these receptors that each specific neurotrophin will act on to maintain the survival of these neurons. Patterning of the receptors was largely based on the stage of embryonic development and where migration ended within the developing DRG. 
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. 
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.  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. Runx3 signalling is usually associated with TrkB+/TrkC+ neurogenesis. 
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 occurring . This timeline represents mouse model of neurogenesis and embryonic developmental days, and these days were converted into the relative human embryonic development days as a reference 
E9.5-E11 (Human: Day 22-33): 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. . These neurons will develop into mechanoceptive and proprioceptive neurons . Ngn-2 expression begins to cease around E10.5, but it overlaps slightly with the time period of condensation into the ganglia structure.
E10.5-13.5 (Human: Day 28-44): 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. . These neurons will develop into nociceptive neurons. . Unlike Ngn-2, Ngn-1 expression did not overlap with condensation, and only is expressed following migration and the condensation into ganglion primordia. 
E12-E13 (Human: Day 28-30): The most rapid proliferation of neurons during the period of neurogenesis. 
E11-E15 (Human: Day 30-54): Sensory neurons undergo apoptosis in order to control concentration levels during development. About half of the newly developed neurons will undergo controlled cell death. Satellite glial cell precursors mostly control the waste that accumulates from this death. 
E13.5-E15.5 (Human: Day 44-55): 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. 
E18.5+ (Human: Day 60+): Sensory neurons undergo maturation. 
Schwann cells are an important glial cells that myelinate peripheral neural axons in order to increase the speed of action potential conduction in the adult peripheral nervous system. In embryonic development, Schwann cell precursors are derived from neural crest cells. Satellite cells, which are also important glial cells that arise during embryonic development, remain in the DRG.  They play a role in controlling the environment surrounding neurons in the DRG, and specifically during the period of apoptosis during neurogenesis, they engulf the decaying material and clear out the excess waste.
The Schwann cell precursors and satellite cell precursors usually emerge about 1.5 days following the beginning of embryonic neuronal development. . 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 .
Neuregulin-1(NRG-1) is also an important signalling molecule that directs the development of Schwann cell precursors into immature Schwann cells and is critical for the survival of the precursors.  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.  Despite the importance of Notch signalling in initial development, in order for myelination properties to emerge, this signalling is be reduced by Krox20(Egr2) activation, since Notch signalling directly opposes myelination onset .
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. 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.  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 . Furthermore, SOX10 regulates the transcription of protein zero, which acts as an integral myelin sheatlh protein for myelination in the peripheral nervous system. When this transcription factor is active on the protein zero promoter, glial cells increase their production of this myelinating protein. When researchers examined the expression in vivo with mice, they demonstrated that mice with a mutated form of the SOX10 gene, there was reduced expression of protein zero in the tissue. The researchers observed a smaller DRG in these mice due to this reduced myelination and a reduced numbers of Schwann cell precursors. 
Timeline of Gliogenesis
This timeline represents mouse model of gliogenesis and embryonic developmental days, and these days were converted into the relative human embryonic development days as a reference .
E10.5 (Human: Day 28): Migration of neural crest cells that will differentiate into glia cells of the DRG begins from the neural tube 
E14-E15 (Human: Day 48-54): Precursors engage with developing axons of the DRG. 
E15-E16 (Human: Day 54-58): Immature Schwann cells develop from Schwann cell precursors. 
E15.5 (Human: Day 55): Krox20 (homologous to Egr2) is expressed, along with other factors specific to myeliantion properties in immature Schwann cells that are destined for myelination within the periphery.  Depending on whether these cells express 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. 
18.5+ (Human: Day 60+): Immature Schwann cells demonstrate non-myelinating or myelinating properties and many reach terminal differentiation. 
Adult Function/Tissue structure
The DRG is the primary structure that transmits sensory information from primary afferent neurons to the spinal cord. It holds the cell bodies of these primary afferent bipolar neurons, and from these neurons, sensory information is transmitted to the central nervous system and processed in both the brain and spinal cord. DRG neurons can process both external stimuli, such as pain, or internal stimuli, such as inflammation. 
In vertebrates, the DRG is a cluster of neurons located in the dorsal root of the spinal cord. It is a bulb-like attachment that emerges from the the dorsal root, containing cell bodies of nerve fibers. These cell bodies are oval in shape and are wrapped completely in sheaths that may include multiple layers of satellite glial cells (SGCs). 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.
Furthermore, the DRG has long axons, known as afferents, that are capable of extending from dendrites on the skin to other tissues and visceral organs throughout the body. Tissues and organs such as the skin , muscles,tendons,joints then to the spinal cord. Lightly myelinated and unmyelinated fibers are positioned on the lateral part of the dorsal root and are small in diameter, relaying pain and temperature sensation. Large myelinated fibers are positioned on the medial part of the dorsal root, which is responsible for transmitting vibration, touch and pressure information.
Signalling Pathways and Molecular Mechanisms
Various signalling pathways and molecular factors contribute to the development of the DRG. Some of the mechanisms which have been studied are briefly described below:
Wnts are signalling molecules that promotes the signalling cascades involved in the development of the embryo and further into adulthood for all animals species  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 . Apart from FZD receptors, Wnt can also bind to receptor tyrosine kinase-like orphan receptors (ROR)  and receptor-like tyrosine kinase (Ryk), which have been shown to be important in regulating axon regeneration .
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 . As a result, β-catenin amass in the cytoplasm before it get transported in the nucleus to initiate the transcription of Wnt-target genes through the formation of a transcriptional activator complex .
β-catenin is a important protein that plays a crucial role in neural crest development and specification of sensory neuronal lineages. Research on mice embryos has shown that the removal of β-catenin leads to the reduction of ngn2-dependent sensory neurons present in the DRG, although it did not have any impact in early Schwann cell differentiation .
ErbB receptors play a role in the development of Schwann cells. These tyrosine kinase receptors are sites for neuregulins (Nrg), a group of epidermal growth factor (EGF)-like motifs, which activates intracellular effector pathways to trigger migration and development of neural crest cells . 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 .
Activation of the ErbB pathway occurs via ligand binding to the extracellular surface of the ErbB receptors, which results in subsequent dimerisation of receptors to activate the tyrosine kinase domain located on the interior the cell. The phosphorylation of activated receptors serves as binding sites for enzymes and proteins downstream of the signalling cascade, resulting in the activation of cellular responses such as proliferation and differentiation .
Early stages of Schwann cell development have been demonstrated to rely on this signalling pathway, along with axonal signal Nrg1 that are derived from close proximal axons. Nrg1 influences a number of factors pertaining to the Schwann cell, such as the promotion of neural crest cells to adopt a glial lineage , expansion and migration of Schwann cell precursor  and providing signals for myelination . Collectively, the Nrg1/ErbB signalling pathway regulates the early period of Schwann cell development and is shown to be required for Schwann cell precursor survival .
Notch is a large transmembrane domain protein that serves as receptor sites for ligands Serrate and Delta and the binding to receptor sites leads to the splitting of the Notch intracellular domain for the subsequent transport of the ligand into the nucleus to activate transcriptional factors that permits cell proliferation and inhibits cell differentiation . The role in DRG development by Notch signalling coincides with its position in suppressing neuronal differentiation and neural crest cell migration . This is done through the process of lateral inhibition and lateral induction.
Lateral inhibition works by inhibiting the production of Notch ligand in neighbouring cells that are in direct contact with a cell that has an activated Notch pathway. The feedback mechanism from neighbouring cells induces a stronger cue that drastically increases the production of ligands from the target cell while causing neighbouring cells to undertake different developmental pathways . On the other hand, having an activated Notch pathway may induce similar activity among neighbouring cells in the process of lateral induction. This results in the similar fate shared among cells that are differentiated, conforming them to the same cell type . In the context of neuronal differentiation, it has been shown that neural crest cells are prevented from undergoing neuronal differentiation with Notch expression, while suppression of the Notch pathway promoted neurogenesis .
Activation of the Notch signalling has been demonstrated to elevate the proportion of non-neuronal cells in the DRG, while its suppression correlates with the increase in number of neurons found in the DRG . A study on mice neural crest cell has demonstrated that Notch pathway may be involved in expressing transcriptional events required for the development of Schwann cell, possibly by directing neural crest cells into a pathway of glial differentiation instead of the dividing precursor state .
Sox genes are a group of transcription factors characterised by their DNA-binding HMG domain and their expression is highly dynamic and conserved . There are 4 major Sox genes that are expressed at the neural plate border, namely Sox8, Sox9, Sox10 and LSox5 , 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 . 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 .
A main characteristic of Sox proteins is their nature of forming complexes with partner transcription factors in order to exhibit gene regulatory functions , 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 . 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 . 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 .
Neurogenins are neuronal determination genes that encodes for base helix-loop-helix (bHLH) transcription factors for neurogenesis. Two main gene types, neurogenin 1 (ngn1) and neurogenin 2 (ngn2), are prominently expressed during neural crest migration and early dorsal root gangliogenesis and the deficiency in both genes would result in the absence of DRG neurons. Notably, constitutive expression of ngn2 by neural crest cells during the early stages of migration suggests the crucial role it plays in DRG development. ngn1 is also demonstrated to be more important as the absence of ngn2 in mutant mice still resulted in the generation of sensory neurons, but at a slower rate . The expression of ngn2 in neural crest cells is shown to promote their migration at the sites of sympathetic ganglion formation lateral to the dorsal aorta .
Runx transcription factor plays a role in designating the specific type of neurons present in DRG. Members of the Runx group of transcription factors acts on the TGF-β superfamily signaling pathway, which activates Smad proteins further down the signalling cascade . The basis of regulation of target genes works by the collaboration of the effect between Runx and Smad that activates the promoter of the gene of interest for later transcription and expression .
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 . Runx3 is also shown to be crucial in managing the axonal projection of DRG neurons  and in the survival and development of DRG neurons . Runx1, on the other hand, is shown to promote TrkA expression in migratory neural crest cells and the development of TrkA+ noncieptive sensory neurons .
Rbpj (Recombination signal binding protein for immunoglobulin kappa J region) is a transcription factor that helps to integrate activation signals from Notch receptors to regulate their transcriptional effects, specifically the inhibition of DRG neuronal differentiation. It interacts with the intracellular domains of all four Notch receptors and is shown to cause disruptions in neurogenesis of Rbpj mutant mice, decreasing cell proliferation and increasing apoptosis .
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, also referred to as ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. There are 4 main types of sensory ganglionitis, a) (1) paraneoplastic sensory neuronopathy, b) subacute sensory neuronopathy associated with Sjögren syndrome, c) chronic ataxic neuropathy associated with paraproteinemia and d) acute sensory neuronopathy syndrome.
These disease is commonly associated with paraproteinemia, neoplasm and Sjögren syndrome. Most people with sensory ganglionitis present their cases sub acutely, but there are possibilities that the disease can develop into a chronic stage. People with these disease shows clinic signs such as sensory ataxia - loss of coordination due to loss of sensory input into movement which is exhibited by gait unsteadiness, an increased loss of balance when asked to close their eyes (Positive Rombert Sign), lowered reflexes in the deep tendon, inability to coordinate oneself, and movement in the hands that are involuntary in nature. Early treatment is definitely needed due to progression of axonal degeneration. Immunosuppression or plasmapheresis can be used to treat patients with this disease, that develop the condition due to immunologic origin The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia. 
Sjögren Syndrome (SS) is commonly associated with a degeneration in the dorsal root ganglion, and presents itself by a prickling/burning sensation in the extremities (paresthesia), lack of body coordination (ataxia), reflexes that are either poor or lack thereof, and inability to keep themselves in balance (Rombert sign). There is usually no loss in muscle strength. Autonomic dysfunction may also be found. Electrophysiological studies reveal a widespread reduction of sensory potential amplitudes, without a distal worsening gradient toward the legs. Asymmetric responses may be observed. Most of the time, motor nerve conduction studies and distal motor amplitudes are normal. Somatosensory evoked potentials may reveal abnormal central conduction times, which are probably due to the degeneration of dorsal root columns in the spinal cord. Magnetic resonance imaging (MRI) has been used as a sensitive technique especially in those patients with long disease duration, showing a hyperintense T2-weighted lesion at posterior columns and volumetric reduction in cervical area resulting from dorsal root degeneration of their projections in the gracile and cuneate fasciculi. Although excisional biopsy of dorsal root ganglion with histological analysis is the gold standard for diagnosis of SN, it is rarely performed due to the possible side effects. Sural nerve biopsy usually shows a massive axonal loss and it is not helpful in the diagnosis.
Primary SS is an autoimmune disease affecting about 1% of the population and more frequently seen in women. It is a systemic disorder characterized by sicca symptomatology of mucosal surfaces. Xerophthalmy and xerostomy are the most frequent symptoms although pulmonary and neurological involvement may also occur. Biologically, patients typically present with hypergammaglobulinemia and positive antinuclear antibodies (ANA) of which anti-SSA and anti-SSB are more specific. Histological main characteristic is a focal lymphocytic infiltration of exocrine glands. Neurological involvement in SS is rare and affects the central and peripheral nervous system. Some series have reported a prevalence of peripheral neuropathy in >50% of patients with SS. The peripheral nervous system involvement occurs in several forms.12–15 In a series of 92 patients with SS-related neuropathies, 39% had SN, 20% small fiber neuropathy, 16% trigeminal neuropathy, 12% multiple mononeuropathies, 5% had multiple cranial neuropathies, 4% had polyradiculoneuropathies, and 3% had autonomic neuropathies.14 Some authors estimate that among all SS patients 5% have SN and 5% to 10% have a small fiber neuropathy. SN is probably less frequent than painful axonal neuropathy. Although less frequent than other forms of peripheral neuropathies, SN causes greater handicap. 
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 
Trunk neural crest migration in the zebrafish is confined to the centre of the medial surface of each somite and the pattern of migration is determined before neural crest cells contacts the sclerotome cells. Unlike other animals such as mice and birds, the sclerotome only makes up an inconsequential part of the somites in zebrafish and did not disrupt neural crest migration and DRG development. 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. 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.
Another key aspect in the proper development of DRG neurons in zebrafish lies in the Sonic hedgehog (Shh) signalling pathway. The Shh protein has been recognised to play an important role in neural tube and somite signalling and is necessary for the development of slow muscle fibres , 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 . The expression of ngn1, in combination with Shh signalling, is thought to be a major influence in promoting neuronal cell development than to fulfil a sensory purpose.
Research has also demonstrated that ErbB3 and ErbB2 are required for Schwann cell migration and myelination in Zebrafish, highlighting the key role of Nrg1/ErbB signaling in the proliferation of Schwann cell precursors and migration along axons . ErbB3 signaling has also been shown to be required for the development of DRG neurons in zebrafish models, as the neural crest cells do not stop at the usual location of DRG formation when ErbB3 ligands are absent .
Current Research (Labs)
Link on current research for DRG 
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  . 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."  .
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).". 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  wanted to know if patients who once used SCS as a treatment for CRPS but were unsuccessful would have success with DRG stimulation for pain relief. The case study concluded that the patients whose t-SCS treatment was unsuccessful felt a great relief of pain when using the DRG-SCS system for treatment .
DRG patch clamp studies
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" 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" . This new approach can be used in the future to study "interactions between primary sensory neurons and satellite glial cells"  . Provided below is a link to the research lab and the video on this procedure.
Dorsalateral - related to the back and side
Dorsa aorta - paired embryological vessels which progress to form the descending aorta
Epithelial-to mesenchymal transition (EMT) - a process where epithelial cells obtain migratory and invasive abilities and becomes mesenchymal stem cells, while losing cell polarity and cell-cell adhesion
Neural crest cells - a group of cells arising from the ectoderm that differentiates into various cell lineages during the development of the embryo
Schwann cells - a glial cell in the peripheral nervous system that wraps around the nerve fiber to forms the myelin sheaths
ventro-lateral - related to the front and side
ventro-medial - related to the front and to the middle
List of Abbreviations
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
SCS: Spinal Chord Stimulation
SHH: Sonic hedgehog
DRG: Dorsal Root Ganglion
                                                                                          
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