Holoprosencephaly represents a common birth defect (1:16,000 in live births and 1:250 in stillbirths) with a broad spectrum of craniofacial malformations ranging from distressful cyclopia to mild symptom of a single central incisor. It is caused by defects in the specification of the ventral forebrain (a part of the anterior axial midline), which subsequently lead to incomplete separation of the brain into the left and right hemispheres. Recent studies indicated that Nodal signaling plays a central role in controlling midline development, we therefore will focus on the regulation of Nodal signaling in mouse embryogenesis with a special interest in anterior axial midline formation. Nodal is a member of the transforming growth factor beta (TGF-beta) superfamily that utilizes a signaling pathway defined by Activin type I and II receptors, Smad2 and 4, and FoxH1(FAST). Importantly, members of the EGF-CFC family of extracellular proteins such as mouse Cripto are essential co-factors for Nodal. We previously reported a Cripto null allele, and recently we generated a Cripto hypomorphic allele, Cripto3-loxP, by genetic manipulation. Approximately 50% of the Cripto3-loxP/CriptoNull mice displayed a wide range of axial midline defects resembling holoprosencephaly. In contrast, TGIF is a homeobox gene encoding a nuclear protein that antagonizes TGF-beta signaling by blocking Smad2 function. Interestingly, mutations in human TGIF gene are associated with holoprosencephaly, suggesting its function in axial midline formation, presumably through regulating Nodal/Smad2 signaling pathway. Based on these results, we will pursue the following specific aims in the proposed research: I) Analysis of the Cripto3-loxP/CriptoNull mice as a model system for ventral forebrain defects and HPE by detailed analysis of the defects in Cripto3-loxP/CriptoNull mice at morphology and molecular levels; II) Investigation of mechanisms underlying Cripto function in mouse axial midline formation by identifying the tissues and cells where Cripto is functioning and downstream target genes of Cripto; III) Investigation of TGIF function in mouse axial midline development by generating TGIF null embryos and examining the modulation of Nodal signaling by TGIF. These studies should improve our understanding of mammalian axial midline formation and human holoprosencephaly.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Scientist Development Award - Research (K02)
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NIDCR Special Grants Review Committee (DSR)
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Hardwick, Kevin S
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University of Louisville
Schools of Dentistry
United States
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Jin, Jiu-Zhen; Ding, Jixiang (2014) Strain-dependent effects of transforming growth factor-?1 and 2 during mouse secondary palate development. Reprod Toxicol 50:129-33
Jin, Jiu-Zhen; Warner, Dennis R; Lu, Qingxian et al. (2014) Deciphering TGF-?3 function in medial edge epithelium specification and fusion during mouse secondary palate development. Dev Dyn 243:1536-43
Jin, Jiu-Zhen; Warner, Dennis R; Ding, Jixiang (2014) Regional divergence of palate medial edge epithelium along the anterior to posterior axis. Int J Dev Biol 58:713-7
Jin, Jiu-Zhen; Tan, Min; Ding, Jixiang (2013) Analysis of Cripto expression during mouse cardiac myocyte differentiation. Int J Dev Biol 57:793-7
Jin, Jiu-Zhen; Ding, Jixiang (2013) Cripto is required for mesoderm and endoderm cell allocation during mouse gastrulation. Dev Biol 381:170-8
Jin, Jiu-Zhen; Tan, Min; Warner, Dennis R et al. (2010) Mesenchymal cell remodeling during mouse secondary palate reorientation. Dev Dyn 239:2110-7
Jin, Jiu-Zhen; Li, Qun; Higashi, Yujiro et al. (2008) Analysis of Zfhx1a mutant mice reveals palatal shelf contact-independent medial edge epithelial differentiation during palate fusion. Cell Tissue Res 333:29-38
Li, Qun; Ding, Jixiang (2007) Gene expression analysis reveals that formation of the mouse anterior secondary palate involves recruitment of cells from the posterior side. Int J Dev Biol 51:167-72
Jin, Jiu-Zhen; Ding, Jixiang (2006) Analysis of cell migration, transdifferentiation and apoptosis during mouse secondary palate fusion. Development 133:3341-7