Bone Morphogenetic Protein (BMP) signaling directs the development of multiple organs and tissues in embryogenesis, and is the causative factor in multiple congenital and adult diseases, including cardiovascular and limb defects, kidney disease, pulmonary hypertension, and is important in medical applications such as orthopedics, endodontics, and tissue engineering. BMP heterodimers have been shown to exhibit consistently higher signaling activity to BMP homodimers and thus are beginning to be used in therapeutics. To understand how BMP signaling can generate diverse cellular responses in a myriad of biological contexts and affect disease, as well as how BMP heterodimers can most effectively be used in therapeutics, it is imperative to understand the mechanism by which they signal. A key function of BMP signaling in vertebrate development is to pattern the cells along the dorsoventral (DV) embryonic axis during late blastula and gastrula stages. BMP signaling activity is thought to act as a morphogen, specifying distinct cell types at different activity levels. Dorsally-emanating BMP antagonists are important in generating the gradient of BMP activity with low levels dorsally and highest levels ventrally. The gradient of BMP signaling activity has now been visualized at high resolution across the DV axis of the vertebrate embryo. Using phosphorylation of Smad5 (P-Smad5) as a direct readout of BMP signaling, a quantitative method was established to measure P-Smad5 levels in all nuclei of the early zebrafish embryo. Using this highly sensitive, reproducible P-Smad5 immunofluorescence assay, the dynamics and overall properties of the signaling gradient have been determined with high precision. The role of the BMP antagonists Chordin, Noggin, and Follistatin in shaping the gradient are being investigated. The studies here will extend these to determine how the gradient is modulated during the extensive morphogenetic movements of gastrulation and how the Chordin inhibitor, the Tolloid and Bmp1a metalloproteases, and their inhibitor Sizzled, modulate the gradient to establish and maintain it throughout gastrulation as the embryo dimensions change dramatically. The exclusive ligand signaling in DV patterning is a Bmp2-Bmp7 heterodimer, which will also be investigated. This BMP heterodimer signals through two distinct classes of BMP Type I receptor, BmpR1 and Acvr1, that are assembled together in a signaling complex. In the previous grant period, it was found that the kinase activities of the Type I receptors differentially function in the signaling complex. The studies here will use the unique in vivo vertebrate model setting of zebrafish DV patterning to elucidate the mechanism of BMP heterodimer signaling, deciphering the specific roles of each Type I receptor in the signaling complex and the roles of the Type II receptors. Altogether the results will be broadly relevant to BMP heterodimer signaling and its modulation in other biological contexts, in their use in the clinic, and in modulating stem cell tissue differentiation in vitro.
The Bone Morphogenetic Protein (BMP) and TGF? family of secreted signaling factors direct the development of multiple organs and tissue types and are implicated in congenital and adult diseases. Ongoing investigations suggest the potential for modulating BMP and TGF? signaling in the treatment of disorders as diverse as kidney disease, pulmonary hypertension, pancreatic, colorectal, and other cancers, and in medical applications such as orthopedics, endodontics, bone regeneration, and tissue engineering. To understand how BMP signaling can generate diverse cellular responses in a myriad of biological contexts and affect disease, it is imperative to understand the mechanism by which BMPs signal and how these signals are regulated in tissue development, as will be studied here.
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