SMAD2 ROLE IN MESODERM FORMATION, LEFT-RIGHT PATTERNING AND CRANIOFACIAL DEVELOPMENT

Signalling by the transforming growth factor-p (TGF-P) superfamily of proteins depends on the phosphorylation and activation of SMAD protein s by heteromeric complexes of ligand-specific type I and type II recep tors with serine/threonine-kinase activity(1). The vertebrate SMAD fam ily includes at least nine members, of which Smad2 has been shown to m ediate signalling by activin and TGF-beta(2-5). In Xenopus, Smad2 can induce dorsal mesoderm, mimicking Vg-1, activin and nodal(2,4), Here w e investigate the function of Smad2 in mammalian development by genera ting two independent Smad2 mutant alleles in mice by gene targeting, W e show that homozygous mutant embryos fail to form an organized egg cy linder and lack mesoderm, like mutant mice lacking nodal(6,7) or ActRI B the gene encoding the activin type-I receptor(8). About 20 per cent of Smad2 heterozygous embryos have severe gastrulation defects and lac k mandibles or eyes, indicating that the gene dosage of Smad2 is criti cal for signalling. Mice trans-heterozygous for both Smad2 and nodal m utations display a range of phenotypes, including gastrulation defects , complex craniofacial abnormalities such as cyclopia, and defects in left-right patterning, indicating that Smad2 may mediate nodal signall ing in these developmental processes. Our results show that Smad2 func tion is essential for early development and for several patterning pro cesses in mice.