2018 Group Project 5

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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

Embryonic Origins

Developmental Process

Neural Crest Migration in Formation of the DRG

Trunk neural crest cells migrate via a ventromedial pathway on the neural tube during the fourth week of development through the anterior somite. Depending on where these cells cease their migratio will determine the structure into which they develop. 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. [1]. 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.[2]Boundary cap neural crest stem cells are some of the transient cells that give rise to the neurons and glia of the DRG.[3].

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

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. TrkA, a nociceptor, and TrkB/TrkC, mechanoreceptors and proprioceptors, are the three classes of neurons that form the DRG following the end of the neural crest migration.[4]. 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.[5].

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.[6] Ngn1 helps to enhance the transcription of the mylinated TrkB,TrkC, and TrkA 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.[5].

Many receptor kinases also aid in the migration and formation of DRG, specifically ErbB family with erbb2 and erbb3.[6]

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[7]. 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[7].

Glial Development

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. Between the cell bodies are layers of satellite glial cells [8].

Tissue / Organ Structure

Molecular Mechanisms / Factors / Genes

CXCR4 Chemokine Receptor

Abnormalities / Abnormal Development

Dorsal Root Ganglionopathy is responsible for the sensory impairment

Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS

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

Zebrafish Model

Neural crest migration and somite development in zebrafish.

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[9]. 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[10]. 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[11].

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[12], 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[13]. 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.

Comparison of neural crest cell migration between erbb3b mutants and wildtype zebrafish models.

Current Research (Labs)

Link on current research for DRG [14]

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 ( 2012 Sapunar et al). 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." ( 2012 Sapunar et al).

Glossary

Reference List

[15] [16] [17] [1] [18] [14] [4] [5] [19] [20] [3] [11] [9] [10] [12] [13] [2] [6] [21]

  1. 1.0 1.1 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.
  2. 2.0 2.1 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
  3. 3.0 3.1 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.
  4. 4.0 4.1 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.
  5. 5.0 5.1 5.2 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.
  6. 6.0 6.1 6.2 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.
  7. 7.0 7.1 Cite error: Invalid <ref> tag; no text was provided for refs named PMID:21549328
  8. Cite error: Invalid <ref> tag; no text was provided for refs named PMID:24641192
  9. 9.0 9.1 Morin-Kensicki EM & Eisen JS. (1997). Sclerotome development and peripheral nervous system segmentation in embryonic zebrafish. Development , 124, 159-67. PMID: 9006077
  10. 10.0 10.1 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.
  11. 11.0 11.1 Honjo Y & Eisen JS. (2005). Slow muscle regulates the pattern of trunk neural crest migration in zebrafish. Development , 132, 4461-70. PMID: 16162652 DOI.
  12. 12.0 12.1 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
  13. 13.0 13.1 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.
  14. 14.0 14.1 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Krames ES. (2014). The role of the dorsal root ganglion in the development of neuropathic pain. Pain Med , 15, 1669-85. PMID: 24641192 DOI.