Our long-term goal is to understand the signals that pattern the early vertebrate embryo, and particularly the role that BMP antagonists play in this process. During previous grant periods, we have identified a number of BMP antagonists that act in early axis formation, mesoderm patterning and neural induction. They are also essential for organogenesis. In the next grant period we will study how these antagonists act, either singly, or more frequently in overlapping combinations, in genetically modified mice. We will use mutant alleles of Noggin and Gremlin, which were both discovered and characterized by our lab, and in addition, we will use mutants of follistatin and chordin. To facilitate the recovery of mutant animals we will use conditional alleles of these genes in combination with Cre drivers. Our particular focus will be the role of the antagonists in development of the somites, gut and skeleton.
A variety of protein antagonists of the Bone Morphogenetic Protein signaling pathway are essential regulators of early development. They affect most organs, but are particularly known for their effects on nervous system, skeleton and stem cell development. They have current uses in stem cell culture, and considerable promise for therapies in clinical disorders such as ectopic bone deposition, all of which justifies a thorough understanding of their role in normal development of the mammalian embryo.
|Stafford, David A; Monica, Stefanie D; Harland, Richard M (2014) Follistatin interacts with Noggin in the development of the axial skeleton. Mech Dev 131:78-85|
|Canalis, Ernesto; Brunet, Lisa J; Parker, Kristen et al. (2012) Conditional inactivation of noggin in the postnatal skeleton causes osteopenia. Endocrinology 153:1616-26|
|Stafford, David A; Brunet, Lisa J; Khokha, Mustafa K et al. (2011) Cooperative activity of noggin and gremlin 1 in axial skeleton development. Development 138:1005-14|
|Harland, Richard M; Grainger, Robert M (2011) Xenopus research: metamorphosed by genetics and genomics. Trends Genet 27:507-15|
|Wills, Andrea E; Choi, Vivian M; Bennett, Margaux J et al. (2010) BMP antagonists and FGF signaling contribute to different domains of the neural plate in Xenopus. Dev Biol 337:335-50|
|Sohaskey, Michael L; Jiang, Yebin; Zhao, Jenny J et al. (2010) Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice. J Cell Biol 189:511-25|
|Sohaskey, Michael L; Yu, Jane; Diaz, Michael A et al. (2008) JAWS coordinates chondrogenesis and synovial joint positioning. Development 135:2215-20|
|Wan, Derrick C; Pomerantz, Jason H; Brunet, Lisa J et al. (2007) Noggin suppression enhances in vitro osteogenesis and accelerates in vivo bone formation. J Biol Chem 282:26450-9|
|Bok, Jinwoong; Brunet, Lisa J; Howard, Omar et al. (2007) Role of hindbrain in inner ear morphogenesis: analysis of Noggin knockout mice. Dev Biol 311:69-78|
|Wills, Andrea; Harland, Richard M; Khokha, Mustafa K (2006) Twisted gastrulation is required for forebrain specification and cooperates with Chordin to inhibit BMP signaling during X. tropicalis gastrulation. Dev Biol 289:166-78|
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