A novel cytokine pathway suppresses glial cell melanogenesis after injury to adult nerve.
The neural crest gives rise to numerous cell types, including Schwann cells, neurons, and melanocytes. The extent to which adult neural crest-derived cells retain plasticity has not been tested previously. We report that cutting adult mouse sciatic nerve induces pigmentation around nerve fascicles, among muscle bundles, and in the hypodermis. Pigmented cells are derived from adult nerve, because pigmentation occurs even when nerve fragments are grafted into tyrosinase null albino mice. Pigmentation defects are pervasive in patients with neurofibromatosis type 1 (NF1). Mice hemizygous for Nf1 mutations show enhanced pigmentation after nerve lesion and occasionally form pigmented and unpigmented tumors. The Nf1 nerve and the Nf1 host environment both contribute to enhanced pigmentation. Grafted purified Nf1 mutant glial cells [S100(+)-p75NGFR(+)-GFAP(+)-EGFR(+) or S100(+)-p75NGFR(+)-GFAP(+)-EGFR(-)] mimic nerve-derived pigmentation. The NF1 protein, neurofibromin, is a Ras-GAP that acts downstream of a few defined receptor tyrosine kinases, including [beta-common (beta(c))] the shared common receptor for granulocyte and monocyte colony-stimulating factor, interleukin-3 (IL3), and IL5. Cytokines in the environment have the potential to suppress pigmentation as shown by nerve injury experiments in null mice; when is beta(c) absent or Nf1 is mutant, melanogenesis is increased. Thus, the adult nerve glial cell phenotype is maintained after nerve injury by response to cytokines, through neurofibromin.
Rizvi
Tilat A
TA
Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267-0521, USA.
Huang
Yuan
Y
Sidani
Amer
A
Atit
Radhika
R
Largaespada
David A
DA
Boissy
Raymond E
RE
Ratner
Nancy
N
D000818:Animals; D019771:Axotomy; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D006579:Heterozygote; D008297:Male; D008543:Melanins / Q000096:biosynthesis*; D008544:Melanocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009409:Nerve Crush; D009432:Neural Crest / Q000166:cytology / Q000196:embryology; D025542:Neurofibromin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D010524:Peripheral Nervous System Neoplasms / Q000150:complications / Q000473:pathology*; D010858:Pigmentation; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D012584:Sciatic Nerve / Q000293:injuries / Q000637:transplantation; D020426:Sciatic Neuropathy / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D008543:Melanins; D025542:Neurofibromin 1