Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo

The Notch ligands D parallel to 1 and D parallel to 3 are coexpressed in the presomitic mesoderm of mouse embryos. Despite their coexpression, mutations in D parallel to 1 and D parallel to 3 cause strikingly different defects. To determine if there is any functional equivalence, we replaced D parallel to 1 with D parallel to 3 in mice. D parallel to 3 does not compensate for D parallel to 1; DLL1 activates Notch in Drosophila wing discs, but DLL3 does not. We do not observe evidence for antagonism between DLL1 and DLL3 or repression of Notch activity in mice or Drosophila. In vitro analyses show that differences in various domains of DLL1 and DLL3 individually contribute to their biochemical non-equivalence. In contrast to endogenous DLL1 located on the surface of presomitic mesoderm cells, we find edogenous DLL3 predominantly in the Golgi apparatus. Our data demonstrate distinct in vivo functions for DLL1 and DLL3 They suggest that DLL3 does not antagonize DLL1 in the presomitic mesoderm and warrant further analyses of potential physiological functions of DLL3 in the Golgi network.