A Dab2 hand in development

The endocytosis of lipoprotein receptors, which mediate the uptake of many protein cargoes by cells, involves specific signals in the receptors. However, which proteins interact with these signals to mediate endocytosis is unclear. Meghan Maurer and Jonathan Cooper now report that endocytosis of the lipoprotein receptor megalin in mouse embryonic visceral endoderm (VE) cells requires Dab2, an adaptor protein that binds to megalin and to endocytic proteins (see p. 5345). Both megalin and Dab2 are expressed in the VE, a polarized epithelium that supplies nutrients to the early embryo. The authors show that endocytosis of megalin and its co-receptor cubilin is greatly reduced in dab^-/- embryos, which arrest before gastrulation. Dab2 has two isoforms – p96 and p67 – and, by making isoform-specific knock-in mice, the authors show that p96 rescues endocytosis and embryonic development more efficiently than p67, which lacks endocytic-protein-binding sites. The authors propose that Dab2 p96 is indispensable in the VE as an adaptor for the endocytosis of megalin and other unidentified receptors that supply the embryo with proteins vital for development.