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J. Biol. Chem., Vol. 283, Issue 37, 25533-25543, September 12, 2008

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Deficiency in Microfibril-associated Glycoprotein-1 Leads to Complex Phenotypes in Multiple Organ Systems^*

Justin S. Weinbaum¹, Thomas J. Broekelmann, Richard A. Pierce, Claudio C. Werneck^¶, Fernando Segade^||, Clarissa S. Craft, Russell H. Knutsen, and Robert P. Mecham²

From the Departments of Cell Biology and Physiology and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, the ^¶Departamento de Bioquimica, Universidade Estadual de Campinas, Campinas 13084-225, Brazil, and the ^||Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6030

Microfibril-associated glycoprotein-1 (MAGP-1) is a small molecular weight component of the fibrillin-rich microfibril. Gene-targeted inactivation of MAGP-1 reveals a complex phenotype that includes increased body weight and size due to excess body fat, an altered wound healing response in bone and skin, and a bleeding diathesis. Elastic tissues rich in MAGP-1-containing microfibrils develop normally and show normal function. The penetrance of MAGP-1-null phenotypes is highly variable and mouse strain-dependent, suggesting the influence of modifier genes. MAGP-1 was found to bind active transforming growth factor-β (TGF-β) and BMP-7 with high affinity, suggesting that it may be an important modulator of microfibril-mediated growth factor signaling. Many of the phenotypic traits observed in MAGP-1-deficient mice are consistent with loss of TGF-β function and are generally opposite those associated with mutations in fibrillin-1 that result in enhanced TGF-β signaling. Increased body size and fat deposition in MAGP-1-mutant animals are particularly intriguing given the localization of obesity traits in humans to the region on chromosome 1 containing the MAGP-1 gene.

Received for publication, December 6, 2007 , and in revised form, July 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL53325, HL71960, HL74138 (to R. P. M.), HL54049 (to R. A. P.), and T32 HL007873 (to J. S. W.). 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 Recipient of a National Science Foundation graduate research fellowship.

² To whom correspondence should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8228, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-2254; Fax: 314-362-2252; E-mail: bmecham{at}wustl.edu.

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