Wounding-Induced Manifestations of Type 1 Neurofibromatosis
Abstract
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 Nfl/nfl 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 1L3/GMCSF shared receptor betac; this suppressive effect is lost in Nfl mutants. We also wounded Nfl/nfl 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 and/or sufficient to promote wound-associated phenotypes of Nfl/nfl 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADB274462
Entities
People
- Nancy Ratner
Organizations
- University of Cincinnati