Editing Schwann cell (section)

== Genetics ==
=== Schwann cell formation ===

==== Sox10 ====
SOX10 is a transcription factor active during embryonic development and abundant evidence indicates that it is essential for the generation of glial lineages from trunk crest cells.<ref name=":0">{{cite journal|last1=Britisch, S.|title=The transcription factor Sox10 is a key regulator of peripheral glial development|journal=Genes Dev.|volume=15|issue=1|pages=66–78|display-authors=etal|doi=10.1101/gad.186601|pmid=11156606|year=2001|pmc=312607}}</ref><ref name=":1">{{cite journal|last1=Paratore, C., Goerich, D. E., Suter, U., Wegner, M. & Sommer, L.|title=Survival and glial fate acquisition of neural crest cells are regulated by an interplay between the transcription factor Sox10 and extrinsic combinatorial signalling|journal=Development|year=2001 |volume=128|issue=20 |pages=3949–61|doi=10.1242/dev.128.20.3949 |pmid=11641219}}</ref> When SOX10 is inactivated in mice, satellite glia and Schwann cell precursors fail to develop, though neurons are generated normally without issue.<ref name=":0" /> In the absence of SOX10, neural crest cells survive and are free to generate neurons, but glial specification is blocked.<ref name=":1" /> SOX10 might influence early glial precursors to respond to neuregulin 1<ref name=":0" /> (see below).

==== Neuregulin 1 ====
Neuregulin 1 (NRG1) acts in a number of ways to both promote the formation and ensure the survival of immature Schwann cells.<ref>{{Cite journal|last=Shah, N. M.|date=1994|title=Glial growth factor restricts mammalian neural crest stem cells to glial fate|journal=Cell|volume=77|issue=3|pages=349–60|doi=10.1016/0092-8674(94)90150-3|pmid=7910115|s2cid=20297598|display-authors=etal}}</ref> During embryonic development, NRG1 inhibits the formation of neurons from neural crest cells, instead contributing to neural crest cells being led down a path to gliogenesis. NRG1 signaling is not, however, required for glial differentiation from the neural crest.<ref name=":2">{{Cite journal|author1=Jessen, K. R.  |author2=Misky, R. |name-list-style=amp |date=2005|title=The origin and development of glial cells in peripheral nerves|journal=Nature Reviews Neuroscience|volume=6|issue=9 |pages=671–82|doi=10.1038/nrn1746|pmid=16136171|s2cid=7540462 }}</ref>

NRG1 plays important roles in the development of neural crest derivatives. It is required for neural crest cells to migrate past the site of dorsal root ganglia to find the ventral regions of sympathetic gangliogenesis.<ref>{{Cite journal|last=Britisch, S.|date=1998|title=The ErbB2 and ErbB3 receptors and their ligand, neuregulin-1 are essential for development of the sympathetic nervous system|journal=Genes Dev.|volume=12|issue=12|pages=1825–36|doi= 10.1101/gad.12.12.1825|pmid=9637684|display-authors=etal|pmc=316903}}</ref> It is also an essential axon-derived survival factor and a mitogen for Schwann cell precursors.<ref>{{Cite journal|last=Dong, Z.|date=1995|title=NDF is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors|journal=Neuron|volume=15|issue=3|pages=585–96|doi=10.1016/0896-6273(95)90147-7|pmid=7546738|s2cid=15332720|display-authors=etal|doi-access=free}}</ref> It is found in the dorsal root ganglion and motor neurons at the point in time that Schwann cell precursors begin to populate spinal nerves and therefore influences Schwann cell survival.<ref name=":2" /> In embryonic nerves, the transmembrane III isoform likely is the primary variant of NRG1 responsible for survival signals. In mice that lack the transmembrane III isoform, Schwann cell precursors are eventually eliminated from spinal nerves.<ref>{{Cite journal|last=Wolpowitz, D.|date=2000|title=Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses|journal=Neuron|volume=25|issue=1|pages=79–91|doi=10.1016/s0896-6273(00)80873-9|pmid=10707974|s2cid=16187922|display-authors=etal|doi-access=free}}</ref>

=== Formation of myelin sheath ===

==== P0 ====
[[Myelin protein zero]] (P0) is a cell-adhesion molecule belonging to the immunoglobulin superfamily and is the major component of peripheral myelin, constituting over 50% of the total protein in the sheath.<ref>{{Cite journal|last1=Greenfield|first1=S.|last2=Brostoff|first2=S.|last3=Eylar|first3=E. H.|last4=Morell|first4=P.|date=1973|title=Protein composition of myelin of the peripheral nervous system|pmid=4697881|journal=Journal of Neurochemistry|volume=20|issue=4|pages=1207–16|doi=10.1111/j.1471-4159.1973.tb00089.x|s2cid=30385476}}</ref><ref>{{Cite journal|last=Lemke|first=G.|date=1988|title=Unwrapping the genes of myelin|journal=Neuron|volume=1|issue=7|pages=535–43|doi=10.1016/0896-6273(88)90103-1|pmid=2483101|s2cid=27086229}}</ref> P0 has been shown to be essential for the formation of compact myelin, as P0 null mutant (P0-) mice showed severely aberrant peripheral myelination.<ref>{{Cite journal|last1=Geise|first1=K.|last2=Martini|first2=R.|last3=Lemke|first3=G|last4=Soriano|first4=P.|last5=Schachner|first5=M.|date=1992|title=Mouse P0 Gene Disruption Leads to Hypomyelination, Abnormal Expression of Recognition Molecules, and Degeneration of Myelin and Axons|journal=Cell|volume=71|issue=4|pages=565–76|doi=10.1016/0092-8674(92)90591-y |pmid=1384988|s2cid=41878912}}</ref>  Although myelination of large caliber axons was initiated in P0- mice, the resulting myelin layers were very thin and poorly compacted.  Unexpectedly, P0- mice also showed degeneration of both axons and their surround myelin sheaths, suggesting that P0 plays a role in maintaining the structural integrity of both myelin formation and the axon with which it is associated.  P0- mice developed behavioral deficits around 2 weeks of age when mice began to show signs of slight trembling.  Gross incoordination also arose as the animals developed, while trembling became more severe and some older mice developed convulsing behaviors.  Despite the array of impaired motor behavior, no paralysis was observed in these animals.  P0 is also an important gene expressed early within the Schwann cell lineage, expressed in Schwann cell precursors after differentiating from migrating [[Neural crest|neural crest cells]] within the developing embryo.<ref>{{Cite journal|last1=Jessen|first1=K.|last2=Mirsky|first2=R.|date=2005|title=The origin and development of glial cells in peripheral nerves|journal=Nature Reviews Neuroscience|volume=6|issue=9|pages=671–82|doi=10.1038/nrn1746|pmid=16136171|s2cid=7540462}}</ref>

==== Krox-20 ====

Several important transcription factors are also expressed and involved at various stages in development changing the features on the Schwann cells from an immature to mature state. One indispensable transcription factor expressed during the myelination process is Krox-20. It is a general zinc-finger transcription factor and is expressed in the rhombomeres 3 and 5.

Krox-20 is considered one of the master regulators of PNS myelination and is important in driving transcription of specific structural proteins in the myelin. It has been shown to control a set of genes responsible for interfering with this feature in the axon changing it from a pro-myelinating to myelinating state.<ref name=":4">{{Cite journal|last=Salzer|first=James|date=2015|title=Schwann cell myelination|journal= Cold Spring Harbor Perspectives in Biology|volume=7|issue=8|pages=a020529|doi=10.1101/cshperspect.a020529|pmid=26054742|pmc=4526746}}</ref> In this way, in Krox-20 double knock out mice, it has been recorded that hindbrain segmentation is affected as well as myelination of Schwann cell associated axons. Indeed, in these mice, the Schwann cells are not able to perform their myelination properly as they only wrap their cytoplasmic processes one and half turn around the axon and despite the fact that they still express the early myelin marker, late myelin gene products are absent. In addition, recent studies have also proven the importance of this transcription factor in maintaining the myelination phenotype (and requires the co-expression of Sox 10) as its inactivation leads to dedifferentiation of the Schwann cells.<ref name=":3">{{Cite journal|last1=Topilko|first1=Piotr|last2=Schneider-Maunoury|first2=Sylvie|last3=Levi|first3=Giovanni|last4=Baron-Van Evercooren|first4=Anne|last5=Chennoufi|first5=Amina Ben Younes|last6=Seitanidou|first6=Tania|last7=Babinet|first7=Charles|last8=Charnay|first8=Patrick|date=1994-10-27|title=Krox-20 controls myelination in the peripheral nervous system|journal=Nature|language=en|volume=371|issue=6500|pages=796–99|doi=10.1038/371796a0|pmid=7935840|bibcode=1994Natur.371..796T|s2cid=4333028}}</ref>