repertoire of cellular interactions and molecular
signaling pathways that control this key dividing
line in the nervous system. These future studies
will likely also provide additional insights into
the roles of transition zones in response to ner-
vous system injury and regeneration. Finally,
some of the cell types and molecules control-
ling axon guidance at theDrosophilaCNS-PNS
boundary have been uncovered ( 93 – 97 ), and
continued study of this interface in multiple
model organisms, including invertebrates, will
contribute to our understanding of the evolu-
tion of CNS-PNS segregation and connectivity.
REFERENCES AND NOTES
- D. S. Barry, J. M. Pakan, K. W. McDermott, Radial glial cells:
Key organisers in CNS development.Int. J. Biochem.
Cell Biol. 46 ,76–79 (2014). doi:10.1016/j.biocel.2013.11.013;
pmid: 24269781 - X. Liuet al., The superficial glia limitans of mouse and monkey
brain and spinal cord.Anat. Rec. 296 , 995–1007 (2013).
doi:10.1002/ar.22717; pmid: 23674345 - D. Ohayonet al., Onset of Spinal Cord Astrocyte Precursor
Emigration from the Ventricular Zone Involves the Zeb1
Transcription Factor.Cell Rep. 17 , 1473–1481 (2016).
doi:10.1016/j.celrep.2016.10.016; pmid: 27806288 - J. P. Fraher, Axon-glial relationships in early CNS-PNS
transitional zone development: An ultrastructural study.
J. Neurocytol. 26 ,41–52 (1997). doi:10.1023/
A:1018511425126; pmid: 9154528 - D. O’Brien, P. Dockery, K. McDermott, J. P. Fraher, The ventral
motoneurone axon bundle in the CNS—A cordone system?
J. Neurocytol. 27 , 247–258 (1998). doi:10.1023/
A:1006932931160; pmid: 10640183 - J. P. Fraher, The CNS-PNS transitional zone of the rat.
Morphometric studies at cranial and spinal levels.Prog.
Neurobiol. 38 , 261–316 (1992). doi:10.1016/0301-0082(92)
90022-7; pmid: 1546164 - P. D. Yurchenco, Basement membranes: Cell scaffoldings and
signaling platforms.Cold Spring Harb. Perspect. Biol. 3 ,
a004911 (2011). doi:10.1101/cshperspect.a004911;
pmid: 21421915 - J. P. Fraher, P. Dockery, O. O’Donoghue, B. Riedewald,
D. O’Leary, Initial motor axon outgrowth from the developing
central nervous system.J. Anat. 211 , 600–611 (2007).
doi:10.1111/j.1469-7580.2007.00807.x; pmid: 17850285 - M. Martins-Green, C. A. Erickson, Development of neural tube
basal lamina during neurulation and neural crest cell
emigration in the trunk of the mouse embryo.J. Embryol. Exp.
Morphol. 98 , 219–236 (1986). pmid: 3655650 - J. A. Siegenthaler, S. J. Pleasure, We have got you‘covered’:
How the meninges control brain development.Curr. Opin.
Genet. Dev. 21 , 249–255 (2011). doi:10.1016/
j.gde.2010.12.005; pmid: 21251809 - G. F. Couly, N. M. Le Douarin, Mapping of the early neural
primordium in quail-chick chimeras. II. The prosencephalic
neural plate and neural folds: Implications for the genesis of
cephalic human congenital abnormalities.Dev. Biol. 120 ,
198 – 214 (1987). doi:10.1016/0012-1606(87)90118-7;
pmid: 3817289 - G. F. Couly, P. M. Coltey, N. M. Le Douarin, The developmental
fate of the cephalic mesoderm in quail-chick chimeras.
Development 114 ,1–15 (1992). pmid: 1576952 - X. Jiang, S. Iseki, R. E. Maxson, H. M. Sucov, G. M. Morriss-Kay,
Tissue origins and interactions in the mammalian skull vault.
Dev. Biol. 241 , 106–116 (2002). doi:10.1006/dbio.2001.0487;
pmid: 11784098 - Y. Choe, J. A. Siegenthaler, S. J. Pleasure, A cascade of
morphogenic signaling initiated by the meninges controls
corpus callosum formation.Neuron 73 , 698–712 (2012).
doi:10.1016/j.neuron.2011.11.036; pmid: 22365545 - K. Zarbalis, Y. Choe, J. A. Siegenthaler, L. A. Orosco,
S. J. Pleasure, Meningeal defects alter the tangential
migration of cortical interneurons in Foxc1hith/hith mice.
Neural Dev. 7 , 2 (2012). doi:10.1186/1749-8104-7-2;
pmid: 22248045 - T. A. C. S. Suter, Z. J. DeLoughery, A. Jaworski, Meninges-
derived cues control axon guidance.Dev. Biol. 430 ,1– 10
(2017). doi:10.1016/j.ydbio.2017.08.005; pmid: 28784295
17. J. P. Fraher, D. C. Bristol, High density of nodes of Ranvier in
the CNS-PNS transitional zone.J. Anat. 170 , 131–137 (1990).
pmid: 2254159
18. A. H. Koeppen, A. B. Becker, J. Qian, B. B. Gelman,
J. E.Mazurkiewicz, Friedreich Ataxia: Developmental Failure of
the Dorsal Root Entry Zone.J. Neuropathol. Exp. Neurol. 76 ,
969 – 977 (2017). doi:10.1093/jnen/nlx087; pmid: 29044418
19. K. J. Radomska, P. Topilko, Boundary cap cells in development
and disease.Curr. Opin. Neurobiol. 47 , 209–215 (2017).
doi:10.1016/j.conb.2017.11.003; pmid: 29174469
20. C. Niederländer, A. Lumsden, Late emigrating neural crest
cells migrate specifically to the exit points of cranial
branchiomotor nerves.Development 122 , 2367–2374 (1996).
pmid: 8756282
21. J. P. Golding, J. Cohen, Border controls at the mammalian
spinal cord: Late-surviving neural crest boundary cap cells at
dorsal root entry sites may regulate sensory afferent ingrowth
and entry zone morphogenesis.Mol. Cell. Neurosci. 9 , 381– 396
(1997). doi:10.1006/mcne.1997.0647; pmid: 9361276
22. F. Coulpieret al., Novel features of boundary cap cells
revealed by the analysis of newly identified molecular
markers.Glia 57 , 1450–1457 (2009). doi:10.1002/glia.20862;
pmid: 19243017
23. C. J. Smith, A. D. Morris, T. G. Welsh, S. Kucenas, Contact-
mediated inhibition between oligodendrocyte progenitor cells
and motor exit point glia establishes the spinal cord transition
zone.PLOS Biol. 12 , e1001961 (2014). doi:10.1371/journal.
pbio.1001961; pmid: 25268888
24. S. Kucenas, W. D. Wang, E. W. Knapik, B. Appel, A selective
glial barrier at motor axon exit points prevents oligodendrocyte
migration from the spinal cord.J. Neurosci. 29 , 15187– 15194
(2009). doi:10.1523/JNEUROSCI.4193-09.2009;
pmid: 19955371
25. D. Nayak, T. L. Roth, D. B. McGavern, Microglia development
and function.Annu. Rev. Immunol. 32 , 367–402 (2014).
doi:10.1146/annurev-immunol-032713-120240;
pmid: 24471431
26. F. Ginhoux, M. Prinz, Origin of microglia: Current concepts and
past controversies.Cold Spring Harb. Perspect. Biol. 7 ,
a020537 (2015). doi:10.1101/cshperspect.a020537;
pmid: 26134003
27. F.A. Court, L. Wrabetz, M. L. Feltri, Basal lamina: Schwann
cells wrap to the rhythm of space-time.Curr. Opin. Neurobiol.
16 , 501–507 (2006). doi:10.1016/j.conb.2006.08.005;
pmid: 16956757
28. W. Halfter, J. Yip, An organizing function of basement
membranes in the developing nervous system.Mech. Dev. 133 ,
1 – 10 (2014). doi:10.1016/j.mod.2014.07.003; pmid: 25058486
29. F. Coulpieret al., CNS/PNS boundary transgression by
central glia in the absence of Schwann cells or Krox20/Egr2
function.J. Neurosci. 30 , 5958–5967 (2010). doi:10.1523/
JNEUROSCI.0017-10.2010; pmid: 20427655
30. I. D. Duncan, R. L. Hoffman, Schwann cell invasion of the
central nervous system of the myelin mutants.J. Anat. 190 ,
35 – 49 (1997). doi:10.1046/j.1469-7580.1997.19010035.x;
pmid: 9034880
31. J. K. Clarket al., MammalianNkx2.2+perineurial glia are
essential for motor nerve development.Dev. Dyn. 243 ,
1116 – 1129 (2014). doi:10.1002/dvdy.24158; pmid: 24979729
32. S. Kucenaset al., CNS-derived glia ensheath peripheral nerves
and mediate motor root development.Nat. Neurosci. 11 ,
143 – 151 (2008). doi:10.1038/nn2025; pmid: 18176560
33. S. Kucenas, Perineurial glia.Cold Spring Harb. Perspect. Biol. 7 ,
a020511 (2015). doi:10.1101/cshperspect.a020511;
pmid: 25818566
34. C. J. Smith, K. Johnson, T. G. Welsh, M. J. Barresi, S. Kucenas,
Radial glia inhibit peripheral glial infiltration into the spinal
cord at motor exit point transition zones.Glia 64 , 1138– 1153
(2016). doi:10.1002/glia.22987; pmid: 27029762
35. F. Fröbet al., Establishment of myelinating Schwann cells and
barrier integrity between central and peripheral nervous
systems depend on Sox10.Glia 60 , 806–819 (2012).
doi:10.1002/glia.22310; pmid: 22337526
36. D. A. Lyonset al., erbb3 and erbb2 are essential for schwann
cell migration and myelination in zebrafish.Curr. Biol. 15 ,
513 – 524 (2005). doi:10.1016/j.cub.2005.02.030;
pmid: 15797019
37. L. Fontenaset al., The Neuromodulator Adenosine Regulates
Oligodendrocyte Migration at Motor Exit Point Transition
Zones.Cell Rep. 27 , 115–128.e5 (2019). doi:10.1016/
j.celrep.2019.03.013; pmid: 30943395
38. Y. Zhu, T. Matsumoto, T. Nagasawa, F. Mackay, F. Murakami,
Chemokine Signaling Controls Integrity of Radial Glial Scaffold
in Developing Spinal Cord and Consequential Proper Position
of Boundary Cap Cells.J. Neurosci. 35 , 9211–9224 (2015).
doi:10.1523/JNEUROSCI.0156-15.2015; pmid: 26085643
- T. J. Sims, S. A. Gilmore, Schwann cells can misdirect
regrowing neuronal processes.Brain Res. 763 ,1 41 – 144 (1997).
doi:10.1016/S0006-8993(97)00501-5; pmid: 9272840 - S. A. Gilmore, T. J. Sims, J. K. Heard, Autoradiographic and
ultrastructural studies of areas of spinal cord occupied by
Schwann cells and Schwann cell myelin.Brain Res. 239 ,
365 – 375 (1982). doi:10.1016/0006-8993(82)90515-7;
pmid: 7093696 - T. J. Sims, S. A. Gilmore, Interactions between intraspinal
Schwann cells and the cellular constituents normally occurring
in the spinal cord: An ultrastructural study in the irradiated rat.
Brain Res. 276 ,17–30 (1983). doi:10.1016/0006-8993(83)
90544-9; pmid: 6626996 - W. F. Blakemore, R. C. Patterson, Observations on the
interactions of Schwann cells and astrocytes following
X-irradiation of neonatal rat spinal cord.J. Neurocytol. 4 ,
573 – 585 (1975). doi:10.1007/BF01351538; pmid: 1177001 - W. F. Blakemore, Invasion of Schwann cells into the spinal cord
of the rat following local injections of lysolecithin.Neuropathol.
Appl. Neurobiol. 2 ,21–39 (1976). doi:10.1111/j.1365-
2990.1976.tb00559.x - L. Jasmin, G. Janni, T. M. Moallem, D. A. Lappi, P. T. Ohara,
Schwann cells are removed from the spinal cord after effecting
recovery from paraplegia.J. Neurosci. 20 , 9215–9223 (2000).
doi:10.1523/JNEUROSCI.20-24-09215.2000; pmid: 11124999 - N. Chaudhryet al., Myelin-Associated Glycoprotein Inhibits
Schwann Cell Migration and Induces Their Death.J. Neurosci.
37 , 5885–5899 (2017). doi:10.1523/JNEUROSCI.1822-16.2017;
pmid: 28522736 - S. Wray, From nose to brain: Development of gonadotrophin-
releasing hormone-1 neurones.J. Neuroendocrinol. 22 ,
743 – 753 (2010). doi:10.1111/j.1365-2826.2010.02034.x;
pmid: 20646175 - P. E. Forni, S. Wray, GnRH, anosmia and hypogonadotropic
hypogonadism—Where are we?Front. Neuroendocrinol. 36 ,
165 – 177 (2015). doi:10.1016/j.yfrne.2014.09.004;
pmid: 25306902 - V. Pingaultet al., Loss-of-function mutations in SOX10 cause
Kallmann syndrome with deafness.Am. J. Hum. Genet. 92 ,
707 – 724 (2013). doi:10.1016/j.ajhg.2013.03.024;
pmid: 23643381 - A. Cariboniet al., Defective gonadotropin-releasing hormone
neuron migration in mice lacking SEMA3A signalling through
NRP1 and NRP2: Implications for the aetiology of
hypogonadotropic hypogonadism.Hum. Mol. Genet. 20 ,
336 – 344 (2011). doi:10.1093/hmg/ddq468; pmid: 21059704 - E. Z. M. Taroc, A. Prasad, J. M. Lin, P. E. Forni, The terminal
nerve plays a prominent role in GnRH-1 neuronal migration
independent from proper olfactory and vomeronasal
connections to the olfactory bulbs.Biol. Open 6 , 1552– 1568
(2017). doi:10.1242/bio.029074; pmid: 28970231 - Y. Toba, J. D. Tiong, Q. Ma, S. Wray, CXCR4/SDF-1 system
modulates development of GnRH-1 neurons and the olfactory
system.Dev. Neurobiol. 68 , 487–503 (2008). doi:10.1002/
dneu.20594; pmid: 18188864 - G. A. Schwarting, T. R. Henion, J. D. Nugent, B. Caplan,
S. Tobet, Stromal cell-derived factor-1 (chemokine C-X-C motif
ligand 12) and chemokine C-X-C motif receptor 4 are required
for migration of gonadotropin-releasing hormone neurons to
the forebrain.J. Neurosci. 26 , 6834–6840 (2006).
doi:10.1523/JNEUROSCI.1728-06.2006; pmid: 16793890 - P. Giacobiniet al., Hepatocyte growth factor acts as a motogen
and guidance signal for gonadotropin hormone-releasing
hormone-1 neuronal migration.J. Neurosci. 27 , 431– 445
(2007). doi:10.1523/JNEUROSCI.4979-06.2007;
pmid: 17215404 - H. Lee, M. R. Song, The structural role of radial glial endfeet in
confining spinal motor neuron somata is controlled by the
Reelin and Notch pathways.Exp. Neurol. 249 ,83–94 (2013).
doi:10.1016/j.expneurol.2013.08.010; pmid: 23988635 - M. Vermerenet al., Integrity of developing spinal motor
columns isregulated by neural crest derivatives at motor exit
points.Neuron 37 , 403–415 (2003). doi:10.1016/S0896-6273
(02)01188-1; pmid: 12575949 - R. Bronet al., Boundary cap cells constrain spinal motor
neuron somal migration at motor exit points by a semaphorin-
plexin mechanism.Neural Dev. 2 , 21 (2007). doi:10.1186/1749-
8104-2-21; pmid: 17971221 - O. Mauti, E. Domanitskaya, I. Andermatt, R. Sadhu,
E. T. Stoeckli, Semaphorin6A acts as a gate keeper between
Suteret al.,Science 365 , eaaw8231 (2019) 30 August 2019 7of8
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