GENETIC ANALYSIS OF MORPHOGENETIC MECHANISM DURING MOUSE DEVELOPMENT

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Developmental process of vertebrate embryos are regulated, at least in part, by secreting molecules such as growth factors. We are focusing on the function of Bone Morphogenetic Proteins (BMPs) that are the members of TGF-beta superfamily during mouse development. To reveal the function of BMP signaling, we have generated a mutant mouse that is deficient for BMP type IA receptor (Bmpr or Alk3) and activin type IA receptor (Alk2) by conventional gene targeting technologies. Nullizygosity of each receptor caused severe embryonic lethality and mutant embryos die at embryonic day 7.5 (Bmpr) or 8.5 (Alk2). For Bmpr mutant embryos, we found that 1) no mesoderm was formed, and 2) cell cycles prior to gastrulation was prolonged. For the Alk2 mutant embryos, we found that 1) mesoderm was formed but not fully differentiated, 2) Alk2 signaling in the extraembryonic region (future placenta) was critical for gastrulation, and 3) Alk2 mutant cells were not capable to contribute heart or eye. These results suggest that BMP signaling at the early stage of embryogenesis is important for cell growth, gastrulation and formation of particular organs such as heart. For the functional analysis of these genes in later stage of development, we introduced a newly invented technology called tissue- specific gene targeting. Using this technology, we mutated Bmpr in bone-specific manner (specific for mature osteoblasts). The bone- specific Bmpr deficient mice were viable indicating we can avoid embryonic lethality of Bmpr mutation by tissue-specific gene targeting technology. Mutant mice were smaller than normal littermate and show irregular calcification and less deposition of bone matrix in their bones. These results are the first evidences that BMP signaling is required for normal bone formation in vivo. We plan to establish tissue-specific mutant mice for Alk3 in following tissues in addition to the bone; neural tissues derived from neural crest cells, hematopoietic organs, cartilage, and developing limb. - TGF-beta, growth factor, embryogenesis, gene targeting, bone morphogenetic protein, neural development