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Wounding-Induced Manifestations of Type 1 Neurofibromatosis

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Final rept. 15 Sep 1997-14 Jun 2001

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Humans with mutations in the NFl gene develop benign peripheral nerve tumors comprised mainly of Schwann cells neurofibromas and hyperpigmented spots on the skin CALM. Mice with mutations of the Nfl gene fail to develop CALM or neurofibromas. We cut the sciatic nerve of Nflnfl mice and induced frequent pigmented spots and rare tumors. We hypothesized that nerve lesion could create an environment triggering abnormal behavior of heterozygous cells including Schwann cells. We tested this hypothesis using nerve grafting. Our data shows mutant Schwann cells form pigment cells in the wound environment. In addition, using mutant mice we show that the environment suppresses pigmentation via the 1L3GMCSF shared receptor betac this suppressive effect is lost in Nfl mutants. We also wounded Nflnfl mice using chemical carcinogenesis and obtained increased pigmentation and keratinocyte tumors, further substantiating our hypothesis that a wound environment can trigger features of human NFl disease. Finally, using transgenic mice, we proposed testing whether Ras activation in peripheral nerve Schwann cells is necessary andor sufficient to promote wound-associated phenotypes of Nflnfl mice. We identified a promoter that drives robust Schwann cell expression, cloned ORD and Ha-Vl2Ras into CNPase promoter-driven plasmids, identified founder mice and for Ras, confirmed overexpression and began phenotype analysis.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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