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J. Biol. Chem., Vol. 281, Issue 8, 5178-5187, February 24, 2006

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Targeting Perlecan in Human Keratinocytes Reveals Novel Roles for Perlecan in Epidermal Formation^*

Ifat Sher¹², Simona Zisman-Rozen¹, Liat Eliahu, John M. Whitelock, Nicole Maas-Szabowski^¶, Yoshihiko Yamada^||, Dirk Breitkreutz^¶, Norbert E. Fusenig^¶, Eri Arikawa-Hirasawa^||, Renato V. Iozzo^**, Reuven Bergman, and Dina Ron³

From the Department of Biology, Technion, Israel Institute of Technology, 32000 Haifa, Israel, Commonwealth Scientific Industrial Research Organization, Molecular Science, North Ryde 2113, Australia, ^¶DKFZ, Division of Differentiation and Carcinogenesis, 69120 Heidelberg, Germany, ^||Craniofacial Developmental Biology and Regeneration Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the ^**Department of Pathology, Anatomy, and Cell Biology, and the Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and the Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Medical Center, 31096 Haifa, Israel

Heparin-binding growth factors are crucial for the formation of human epidermis, but little is known about the role of heparan sulfate proteoglycans in this process. Here we investigated the role of the heparan sulfate proteoglycan, perlecan, in the formation of human epidermis, by utilizing in vitro engineered human skin. By disrupting perlecan expression either in the dermis or the epidermis, we found that epidermally derived perlecan is essential for epidermal formation. Perlecan-deficient keratinocytes formed a strikingly thin and poorly organized epidermis because of premature apoptosis and failure to complete their stratification program. Exogenous perlecan fully restored epidermal formation. Perlecan deposition in the basement membrane zone correlated with formation of multilayered epidermis. Perlecan deficiency, however, had no effect on the lining and deposition of major basement membrane components as was evident by a continuous linear staining of laminin and collagen IV. Similarly, perlecan deficiency did not affect the distribution of 1 integrin. Addition of the perlecan ligand, fibroblast growth factor 7, protected perlecan-deficient keratinocytes from cell death and improved the thickness of the epidermis. Taken together, our results revealed novel roles for perlecan in epidermal formation. Perlecan regulates both the survival and terminal differentiation steps of keratinocytes. Our results suggested a model whereby perlecan regulates these processes via controlling the bioavailability of perlecan-binding soluble factors involved in epidermal morphogenesis.

Received for publication, August 29, 2005 , and in revised form, November 1, 2005.

^* This work was supported by DKFZ Grant 140-623, Israel Science Foundation (ICRF) Grants 140-755 and 200-4973 (to D. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Biomedical Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada.

³ To whom correspondence should be addressed: Dept. of Biology, Technion, Israel Institute of Technology, Haifa 32000, Israel. Tel.: 972-4-8294217; Fax: 972-4-8225153; E-mail: dinar{at}tx.technion.ac.il.

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