The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited by fibroblasts

Radhika P. Atit, Maria J. Crowe, David G Greenhalgh, Richard J. Wenstrup, Nancy Ratner

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Neurofibromatosis type 1 patients develop peripheral nerve tumors (neurofibromas) composed mainly of Schwann cells and fibroblasts, in an abundant collagen matrix produced by fibroblasts. Trauma has been proposed to trigger neurofibroma formation. To test if loss of the neurofibromatosis type 1 gene (Nf1) compromises fibroblast function in vivo following trauma, skin wounding was performed in Nf1 knockout mice. The pattern and amount of collagen-rich granulation bed tissue, manufactured by fibroblasts, was grossly abnormal in 60% of Nf1+/- wounds. Nf1 mutant fibroblasts showed cell autonomous abnormalities in collagen deposition in vitro that were not mimicked by Ras activation in fibroblasts, even though some Nf1 effects are mediated through Ras. Nf1+/- skin wound fibroblasts also proliferated past the normal wound maturation phase; this in vivo effect was potentiated by muscle injury. In vitro, Nf1+/- fibroblasts showed higher proliferation in 10% serum than Nf1+/+ fibroblasts. Macrophage-conditioned media or epidermal growth factor potentiated Nf1+/- fibroblast proliferation in vitro, demonstrating abnormal response of mutant fibroblasts to wound cytokines. Thus Nf1 is a key regulator of fibroblast responses to injury, and Nf1 mutation in mouse fibroblasts causes abnormalities characteristic of human neurofibromas.

Original languageEnglish (US)
Pages (from-to)835-842
Number of pages8
JournalJournal of Investigative Dermatology
Volume112
Issue number6
DOIs
StatePublished - 1999

Keywords

  • Epidermal growth factor
  • Macrophage
  • Neurofibromin
  • Ras

ASJC Scopus subject areas

  • Dermatology

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