A Novel Cytokine Pathway Suppresses Glial Cell Melanogenesis after Injury to Adult Nerve

Abstract

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.

MicroRNA Inhibitors as Anticancer Therapies

“…Although the transformed Nf1 -/-Schwann cells (Nf1 -/-TXF) exhibited hyperplasia in vitro when exposed to forskolin or withdrawal of serum from the culture medium , they did not show tumor formation in mouse nerve (Rizvi et al, 2002), in contrast to our results. We found Nf1 -/-Schwann cells (both SSC and FSC) showed a growth advantage in medium not only with low levels of serum but also with high levels of serum and no forskolin.…”

“…These models also take up to 1 year for tumors to develop, and the tumor sites are unpredictable. Our examination of Nf1 -/-Schwann cells engrafted into Nf1 þ/-nerves up to 12 weeks postimplantation showed limited growth and no significant tumor masses, which is similar to the observations by Rizvi et al (2002). However, more detailed histological and immunohistochemical analysis showed that Nf1 -/-Schwann cells syngrafts have significantly increased cellularity and mitotic index compared with control grafts, indicating a potential tumorigenic growth.…”

“…In contrast, syngrafted Nf1 þ/-Schwann cells are not expansive and actually decrease over time, indicating that they are not tumorigenic. Although injury-induced tumor growth has been found occasionally in Nf1 þ/-mice following nerve transection (Rizvi et al, 2002), the absence of tumor formation in our Nf1 þ/-Schwann cell grafts makes it very unlikely that the cell injection per se or any allogenic response initiated tumorigenic growth by the engrafted Nf1 -/-Schwann cells.…”

Mechanisms and Roles of Axon-Schwann Cell Interactions

“…Nf1 Ϫ/Ϫ mouse embryos die by E14.5, and adult Nf1 ϩ/Ϫ mice do not spontaneously develop neurofibromas. However, neurofibromas formed when Nf1 Ϫ/Ϫ embryonic stem cells were added to wild-type blastocysts (Cichowski et al, 1999) or after wounding of Nf1 ϩ/Ϫ peripheral nerves (Rizvi et al, 2002). Moreover, when dorsal root ganglion cells are purified from Nf1 mutant embryos at E12.5, the Nf1 ϩ/Ϫ and Nf1…”

“…Notably, an additional morphologically transformed, fastgrowing, p75NGFR, S100␤, and GFAP-expressing subpopulation of cells, denoted Nf1 Ϫ/Ϫ TXF, is also present in these cultures (Kim et al, 1997;Rizvi et al, 2002). These cells have been used as a model of neurofibroma formation.…”