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Published online on November 17, 2006, 10.1073/pnas.0608899103
PNAS | November 28, 2006 | vol. 103 | no. 48 | 18166-18171


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BIOLOGICAL SCIENCES / DEVELOPMENTAL BIOLOGY
Bone morphogenetic protein signaling regulates the size of hair follicles and modulates the expression of cell cycle-associated genes

Andrey A. Sharov*, Tatyana Y. Sharova*, Andrei N. Mardaryev*, Alice Tommasi di Vignano{dagger}, Ruzanna Atoyan*, Lorin Weiner{dagger}, Shi Yang{ddagger}, Janice L. Brissette{dagger}, G. Paolo Dotto{dagger},§, and Vladimir A. Botchkarev*,¶,||

Departments of *Dermatology and {ddagger}Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118; {dagger}Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129; §Department of Biochemistry, Lausanne University, CH-1066 Lausanne, Switzerland; and Medical Biosciences, School of Life Sciences, University of Bradford, Bradford BD7 1DP, United Kingdom

Communicated by Elaine Fuchs, The Rockefeller University, New York, NY, October 8, 2006 (received for review February 7, 2006)

Bone morphogenetic protein (BMP) signaling is involved in the regulation of a large variety of developmental programs, including those controlling organ sizes. Here, we show that transgenic (TG) mice overexpressing the BMP antagonist noggin (promoter, K5) are characterized by a marked increase in size of anagen hair follicles (HFs) and by the replacement of zig-zag and auchen hairs by awl-like hairs, compared with the age-matched WT controls. Markedly enlarged anagen HFs of TG mice show increased proliferation in the matrix and an increased number of hair cortex and medulla cells compared with WT HFs. Microarray and real-time PCR analyses of the laser-captured hair matrix cells show a strong decrease in expression of Cdk inhibitor p27Kip1 and increased expression of selected cyclins in TG vs. WT mice. Similar to TG mice, p27Kip1 knockout mice also show an increased size of anagen HFs associated with increased cell proliferation in the hair bulb. Primary epidermal keratinocytes (KC) from TG mice exhibit significantly increased proliferation and decreased p27Kip1 expression, compared with WT KC. Alternatively, activation of BMP signaling in HaCaT KC induces growth arrest, stimulates p27Kip1 expression, and positively regulates p27Kip1 promoter activity, thus further supporting a role of p27Kip1 in mediating the effects of BMP signaling on HF size. These data suggest that BMP signaling plays an important role in regulating cell proliferation and controls the size of anagen HFs by modulating the expression of cell-cycle-associated genes in hair matrix KC.

Noggin | proliferation | skin

Author contributions: A.A.S. and T.Y.S. contributed equally to this work; V.A.B. designed research; A.A.S., T.Y.S., A.N.M., A.T.d.V., R.A., and L.W. performed research; A.A.S., T.Y.S., A.N.M., A.T.d.V., L.W., S.Y., J.L.B., and G.P.D. contributed new reagents/analytic tools; A.A.S., T.Y.S., A.N.M., R.A., and V.A.B. analyzed data; and V.A.B. wrote the paper.

The authors declare no conflict of interest.

||To whom correspondence should be addressed. E-mail: vladbotc{at}bu.edu

© 2006 by The National Academy of Sciences of the USA


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