Developmental process of vertebrate embryos is 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 functional analysis of these gene products in a later stage of development, we introduced a newly invented technology called tissue-specific gene targeting. Using this technology, we mutated Bmpr in a bone-specific manner (specific for mature osteoblasts), in collaboration with Dr. Gerard Karsenty, Baylor College of Medicine. The bone-specific Bmpr deficient mice were viable indicating we can avoid embryonic lethality of Bmpr disruption with 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. In another approach, we mutated Bmpr in a neural crest specific manner, in collaboration with Drs. Yasutaka Yamauchi and Ken-ichi Yamamura, Kumamoto University. Embryos die at the mid-gestation stage showing abnormalities in neural crest cell-derived tissues. We also mutated Bmpr in a neural-precursor specific manner at the stage of gastrulation, in collaboration with Dr. Philipe Soriano, Fred Hutchinson Cancer Center. Embryos showed an overgrowth of neural tissues after gastrulation. These results indicate that BMP signaling plays a critical role in various stage of neural tissue development.
Showing the most recent 10 out of 85 publications
