Deficiency in microfibril-associated glycoprotein-1 leads to complex phenotypes in multiple organ systems.
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-beta (TGF-beta) 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-beta function and are generally opposite those associated with mutations in fibrillin-1 that result in enhanced TGF-beta 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.
Weinbaum
Justin S
JS
Departments of Cell Biology and Physiology, St. Louis, Missouri 63110.
Broekelmann
Thomas J
TJ
Departments of Cell Biology and Physiology, St. Louis, Missouri 63110.
Pierce
Richard A
RA
Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Werneck
Claudio C
CC
Departamento de Bioquimica, Universidade Estadual de Campinas, Campinas 13084-225, Brazil.
Segade
Fernando
F
Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6030.
Craft
Clarissa S
CS
Departments of Cell Biology and Physiology, St. Louis, Missouri 63110.
Knutsen
Russell H
RH
Departments of Cell Biology and Physiology, St. Louis, Missouri 63110.
Mecham
Robert P
RP
Departments of Cell Biology and Physiology, St. Louis, Missouri 63110. Electronic address: bmecham@wustl.edu.
D000818:Animals; D001835:Body Weight; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D003285:Contractile Proteins / Q000235:genetics* / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020894:Microfibrils / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D000072260:RNA Splicing Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054392:Adipokines
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D003285:Contractile Proteins; D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D000072260:RNA Splicing Factors; D016212:Transforming Growth Factor beta; C525819:BMP7 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C016598:microfibrillar protein