N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGF{beta} pathways

TY - JOUR

T1 - N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGF{beta} pathways

AU - Lefever, Tine

AU - Pedersen, Esben

AU - Basse, Astrid

AU - Paus, Ralf

AU - Quondamatteo, Fabio

AU - Stanley, Alanna C

AU - Langbein, Lutz

AU - Wu, Xunwei

AU - Wehland, Jürgen

AU - Lommel, Silvia

AU - Brakebusch, Cord

N1 - Keywords: Alopecia; Animals; Cell Cycle; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p21; Hair Follicle; Keratinocytes; Mice; Microfilaments; Morphogenesis; Signal Transduction; Transforming Growth Factor beta; Wiskott-Aldrich Syndrome Protein, Neuronal

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

U2 - 10.1242/jcs.053835

DO - 10.1242/jcs.053835

M3 - Journal article

C2 - 20016073

SN - 0021-9533

VL - 123

SP - 128

EP - 140

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - Pt 1

ER -