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First published online December 16, 2009
doi: 10.1242/jcs.053835

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N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

¹ Biomedical Institute, University of Copenhagen, 2200 Copenhagen, Denmark
² BRIC, University of Copenhagen, 2200 Copenhagen, Denmark
³ University of Ghent, 9052 Gent (Zwijnaarde), Belgium
⁴ Department of Dermatology, Allergology and Venerology, University of Lübeck, 23538 Lübeck, Germany
⁵ School of Translational Medicine, University of Manchester, Manchester, UK
⁶ Department of Anatomy, National University of Ireland, Galway, Ireland
⁷ German Cancer Research Center (DKFZ), Genetics of Skin Carcinogenesis (A110), 69120 Heidelberg, Germany
⁸ Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
⁹ Institute for Cell Biology, University of Bonn, 53121 Bonn, Germany

^* Author for correspondence (cord.brakebusch{at}bric.dk)

Accepted 15 April 2009

N-WASP is a cytoplasmic molecule mediating Arp2/3 nucleated actin polymerization. Mice with a keratinocyte-specific deletion of the gene encoding N-WASP showed normal interfollicular epidermis, but delayed hair-follicle morphogenesis and abnormal hair-follicle cycling, associated with cyclic alopecia and prolonged catagen and telogen phases. The delayed anagen onset correlated with an increased expression of the cell-cycle inhibitor p21CIP, and increased activity of the TGFβ pathway, a known inducer of p21CIP expression. Primary N-WASP-null keratinocytes showed reduced growth compared with control cells and enhanced expression of the gene encoding the cell-cycle inhibitor p15INK4B, a TGFβ target gene. Inhibition of TGFβ signaling blocked overexpression of p15INK4B and restored proliferation of N-WASP-deficient keratinocytes in vitro. However, induction of N-WASP gene deletion in vitro did not result in obvious changes in TGFβ signaling or growth of keratinocytes, indicating that the in vivo environment is required for the phenotype development. These data identify the actin nucleation regulator N-WASP as a novel element of hair-cycle control that modulates the antiproliferative and pro-apoptotic TGFβ pathway in keratinocytes in vivo and in vitro.

Key words: N-WASP, Hair cycling, Keratinocytes

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