Although the function of some inner nuclear membrane proteins is known, the function of others - including Man1 - remains unclear. Man1 negatively regulates Tgfβ signalling by interacting with receptor-associated Smads in cultured cells. But what is its role in vivo? On , Ishimura and colleagues propose that Man1 regulates angiogenesis during mouse embryogenesis by interacting with Smads. Their findings show that embryos in which the Smad-interaction domain of Man1 is deleted die at midgestation, owing to defects in their embryonic vasculature. They report that increased Smad2/3 signalling and Tgfβ1 expression in these Man1-deficient embryos cause increased extracellular matrix (ECM) deposition, as is also seen in people with MAN1 mutations. This increased ECM deposition probably inhibits endothelial cell proliferation and migration; the recruitment of smooth muscle cells to the vascular wall is also disturbed. Together, these results suggest that Man1 regulates embryonic vascular remodelling by interacting with receptor-associated Smads at the inner nuclear membrane to ultimately modulate Tgfβ signalling.
