A significant number of human craniofacial syndromes are the result of abnormal development of the first (mandibular) branchial arch (BA1). Most of BA1 mesenchyme is derived from cephalic neural crest cells (NCC) that emerge from the lateral edges of the neural folds, migrate ventrally in close proximity to the developing pharynx, and populate BA1 primordia. At the level of BA1, NCCs receive signals from the local environment that regulate their proliferation, survival, and differentiation. Multiple developmental pathways are involved in regulating morphogenesis of BA1, with bone morphogenetic proteins (BMPs) playing a prominent role. Twsg1 is a secreted protein that binds to BMPs and modulates their activities. We have shown that Twsg1-deficient mice have abnormal morphogenesis of BA1, manifesting as agnathia, with variable degrees of accompanying craniofacial defects. Twsg1 mutant mice also show defects in foregut endoderm suggesting that Twsg1 signaling is necessary for foregut development. Our long-range goal is to understand molecular mechanisms underlying human craniofacial syndromes. The objective of the present study is to characterize the role of Twsg1 in mandibular arch morphogenesis. Our central hypothesis is that Twsg1 is required for morphogenesis of the medial region of BA1 and that foregut endoderm deficiency in Twsg1-/- mice affects patterning of cephalic NCC. The rationale for the proposed research is that knowledge obtained from this study will promote our understanding of the molecular and cellular basis of BA1 patterning that can ultimately lead to better diagnosis of human craniofacial syndromes, which result from abnormal development of BA1. Our studies will also inform how precise regulation of BMP signaling affects complex patterning events, such as those required for mandibular development. The following specific aims will be pursued: 1) Examine cephalic NCC formation and migration and mandibular arch morphogenesis in Twsg1-/- mice by using NCC- and BA1-specific markers, as well as assays of proliferation and apoptosis;2) Identify genes regulated by Twsg1 signaling in BA1 development by using microarray technology;3) Identify the cells that are the primary target of Twsg1 gene action in patterning of BA1 by generating endoderm-specific deletion of Twsg1;4) Understand how excess of Twsg1 affects molecular boundaries of BMP signaling during BA1 morphogenesis by implanting Twsg1-soaked beads into mouse mandibular explants. Lay summary: Abnormal development of the lower jaw is a common finding in children with various craniofacial syndromes. We have identified a gene, Twsg1, that is important for jaw development in mice. Since Twsg1 gene is also present in humans and lower jaw development is similar in mice and humans, this work can lead to better understanding and ultimately diagnosis of human craniofacial syndromes.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Scholnick, Steven
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University of Minnesota Twin Cities
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Huntley, Raphael; Davydova, Julia; Petryk, Anna et al. (2015) The Function of Twisted Gastrulation in Regulating Osteoclast Differentiation is Dependent on BMP Binding. J Cell Biochem 116:2239-46
Billington Jr, Charles J; Schmidt, Brian; Marcucio, Ralph S et al. (2015) Impact of retinoic acid exposure on midfacial shape variation and manifestation of holoprosencephaly in Twsg1 mutant mice. Dis Model Mech 8:139-46
Akiyama, Ryutaro; Kawakami, Hiroko; Taketo, M Mark et al. (2014) Distinct populations within Isl1 lineages contribute to appendicular and facial skeletogenesis through the ?-catenin pathway. Dev Biol 387:37-48
Forsman, Cynthia L; Ng, Brandon C; Heinze, Rachel K et al. (2013) BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization. Dev Biol 373:95-106
Billington Jr, Charles J; Schmidt, Brian; Zhang, Lei et al. (2013) Maternal diet supplementation with methyl donors and increased parity affect the incidence of craniofacial defects in the offspring of twisted gastrulation mutant mice. J Nutr 143:332-9
Broege, Aaron; Pham, Lan; Jensen, Eric D et al. (2013) Bone morphogenetic proteins signal via SMAD and mitogen-activated protein (MAP) kinase pathways at distinct times during osteoclastogenesis. J Biol Chem 288:37230-40
Pham, Lan; Beyer, Kayla; Jensen, Eric D et al. (2011) Bone morphogenetic protein 2 signaling in osteoclasts is negatively regulated by the BMP antagonist, twisted gastrulation. J Cell Biochem 112:793-803
Billington Jr, Charles J; Ng, Brandon; Forsman, Cynthia et al. (2011) The molecular and cellular basis of variable craniofacial phenotypes and their genetic rescue in Twisted gastrulation mutant mice. Dev Biol 355:21-31
Jensen, Eric D; Pham, Lan; Billington Jr, Charles J et al. (2010) Bone morphogenic protein 2 directly enhances differentiation of murine osteoclast precursors. J Cell Biochem 109:672-82
Sun, M; Forsman, C; Sergi, C et al. (2010) The expression of twisted gastrulation in postnatal mouse brain and functional implications. Neuroscience 169:920-31

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