Microfibril-associated glycoprotein-2 (MAGP-2) is one of two MAGPs, both of which are integral components of microfibrils associated with elastic fibers. MAGP-2 is shown herein to bind specifically to fibrillin-1 and -2, two well-characterized constituents of extracellular microfibrils that are genetically linked to heritable disorders of elastic fibers known as the Marfan syndrome and congenital contractural arachnodactyly, respectively. MAGP-2 also binds MAGP- 1. In this proposal, the function of MAGP-2 within the microfibril will be examined. MAGP-2 binding sites on both fibrillin-1 and MAGP-1 will be localized, as will determinants within MAGP-2 responsible for these. The spatial and temporal pattern of MAGP-2 gene expression in the developing mouse will be determined, and coexpression/colocalization with other major elastic fiber components will be assessed. MAGP-2 expression in the MAGP-1 knockout mouse will also be investigated. A mouse harboring a targeted disruption of the MAGP-2 gene will be generated and assessed for developmental abnormalities. Microfibrils in MAGP-2 -/- mice will be studied at the ultrastructural level. If the mouse dies during embryonic development, primary fibroblast cultures will be derived from MAGP-2 -/- lungs and used to study the role of MAGP-2 in microfibril assembly in vitro. The role of MAGP-2 in lung branching morphogenesis will also be studied in knockouts should their lungs develop abnormally. If the MAGP-2 -/- mice lack an overt phenotype, they will be bred with MAGP-1 knockout mice to make mice lacking both MAGPs to assess whether the MAGPs have overlapping yet critical functions.
| Nehring, Leslie C; Miyamoto, Alison; Hein, Patrick W et al. (2005) The extracellular matrix protein MAGP-2 interacts with Jagged1 and induces its shedding from the cell surface. J Biol Chem 280:20349-55 |
| Krymskaya, Vera P; Shipley, J Michael (2003) Lymphangioleiomyomatosis: a complex tale of serum response factor-mediated tissue inhibitor of metalloproteinase-3 regulation. Am J Respir Cell Mol Biol 28:546-50 |
| Penner, Akiyo S; Rock, Matthew J; Kielty, Cay M et al. (2002) Microfibril-associated glycoprotein-2 interacts with fibrillin-1 and fibrillin-2 suggesting a role for MAGP-2 in elastic fiber assembly. J Biol Chem 277:35044-9 |
