Functional analysis of zebrafish Microfibril-Associated Glycoprotein-1 (MAGP-1) in vivo reveals roles for microfibrils in both vascular development and function

Mutations in fibrillin-1 result in Marfan Syndrome, demonstrating a critical requirement for microfibrils in vessel structure and function. However, the identity and function of many microfibril-associated molecules essential for vascular development and function have yet to be characterized. In our morpholino-based screen for members of the secretome required for vascular development, we identified a key player in microfibril formation in zebrafish embryogenesis. Microfibril-Associated Glycoprotein-1 (MAGP-1) is a conserved protein found in mammalian and zebrafish microfibrils. Expression of MAGP-1 mRNA is detected in microfibril-producing cells. Analysis of a functional MAGP-1-mRFP fusion protein reveals localization along the midline and in the vasculature during embryogenesis. Under- and over- expression analysis demonstrates that specific MAGP-1 protein levels are critical for vascular development. Integrin function is compromised in MAGP-1 morphant embryos, suggesting that reduced integrin/matrix interaction is the main mechanism for the vascular defects in MAGP1 morphants. We further show that MAGP-1 and Fibrillin-1 interact in vivo. This study implicates MAGP-1 as a key player in microfibril formation and integrity during development. The essential role for MAGP-1 in vascular morphogenesis and function also supports a wide range of clinical applications including therapeutic targets in vascular disease and cardiovascular tissue engineering.