BONE MORPHOGENETIC PROTEIN-4 IS REQUIRED FOR MESODERM FORMATION AND PATTERNING IN THE MOUSE

Bone morphogenetic protein-4 (BMP-4) is a member of the TGF-beta super family of polypeptide signaling molecules, closely related to BMP-2 an d to Drosophila decapentaplegic (DPP). To elucidate the role of BMP-4 in mouse development the gene has been inactivated by homologous recom bination in ES cells. Homozygous mutant Bmp-(4tm1blh) embryos die betw een 6.5 and 9.5 days p.c., with a variable phenotype. Most Bmp-(4tm1bl h) embryos do not proceed beyond the egg cylinder stage, do not expres s the mesodermal marker T(Brachyury), and show little or no mesodermal differentiation. Some homozygous mutants develop to the head fold or beating heart/early somite stage or beyond. However, they are developm entally retarded and have truncated or disorganized posterior structur es and a reduction in extraembryonic mesoderm, including blood islands . These results provide direct genetic evidence that BMP-4 is essentia l for several different processes in early mouse development, beginnin g with gastrulation and mesoderm formation. Moreover, in the presumed absence of zygotic ligand, it appears that homozygous mutants can be r escued partially by related proteins or by maternal BMP-4.