The Bone Morphogenetic Protein (BMP) family of secreted signaling molecules directs the development of multiple organs and tissue types at various stages in embryogenesis, and is implicated in congenital and adult diseases. Enormous insights into the physiologic roles of BMP signaling have been gained through their study in model organisms, which have vastly enhanced our understanding of human development and disease. Here the nature of the BMP signaling complex will be explored that functions during gastrulation to pattern tissues along the vertebrate dorsal- ventral axis. The long-term goal is to understand the molecular basis for the requirement for multiple ligands and receptors to transduce BMP signaling. Second the coordination of patterning along the dorsal-ventral and anterior-posterior axes will be investigated, testing the hypothesis that patterning of these two axes is coordinated. It is postulated that this coordinate patterning results in BMP activity acting progressively over time along the anterior-posterior axis to pattern dorsal-ventral tissues. Lastly, the molecular nature and contributions of a new recessive dorsalized, maternal-effect mutant gene, will be studied, to maximize our understanding of the genetic regulation of BMP signaling in development and disease through loss-of-function studies. Thus it is critical to identify and study all the genetic players in this process. Public Health Relevance: The Bone Morphogenetic Protein (BMP) and TGF2 family of secreted signaling molecules directs the development of multiple organs and tissue types and is implicated in congenital and adult diseases. Ongoing investigations suggest the potential for modulating BMP and TGF2 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, and tissue engineering. Our understanding of the physiologic roles of BMP and TGF2 signaling in development and disease requires thorough studies of the means by which their signaling generates diverse cellular responses in a myriad of biological contexts, as will be studied here.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Development - 2 Study Section (DEV2)
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Haynes, Susan R
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Mucha, Bettina E; Hashiguchi, Megumi; Zinski, Joseph et al. (2018) Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone 109:225-231
Tajer, Benjamin; Mullins, Mary C (2017) Heterodimers reign in the embryo. Elife 6:
Zinski, Joseph; Bu, Ye; Wang, Xu et al. (2017) Systems biology derived source-sink mechanism of BMP gradient formation. Elife 6:
Escobar-Aguirre, Matias; Elkouby, Yaniv M; Mullins, Mary C (2017) Localization in Oogenesis of Maternal Regulators of Embryonic Development. Adv Exp Med Biol 953:173-207
Langdon, Yvette G; Fuentes, Ricardo; Zhang, Hong et al. (2016) Split top: a maternal cathepsin B that regulates dorsoventral patterning and morphogenesis. Development 143:1016-28
Elkouby, Yaniv M; Jamieson-Lucy, Allison; Mullins, Mary C (2016) Oocyte Polarization Is Coupled to the Chromosomal Bouquet, a Conserved Polarized Nuclear Configuration in Meiosis. PLoS Biol 14:e1002335
Tuazon, Francesca B; Mullins, Mary C (2015) Temporally coordinated signals progressively pattern the anteroposterior and dorsoventral body axes. Semin Cell Dev Biol 42:118-33
Ge, Xiaoyan; Grotjahn, Danielle; Welch, Elaine et al. (2014) Hecate/Grip2a acts to reorganize the cytoskeleton in the symmetry-breaking event of embryonic axis induction. PLoS Genet 10:e1004422
Kapp, Lee D; Abrams, Elliott W; Marlow, Florence L et al. (2013) The integrator complex subunit 6 (Ints6) confines the dorsal organizer in vertebrate embryogenesis. PLoS Genet 9:e1003822
Hashiguchi, Megumi; Mullins, Mary C (2013) Anteroposterior and dorsoventral patterning are coordinated by an identical patterning clock. Development 140:1970-80

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