This is a R03 application focused on the initial characterization of TGIF knockout mice and the use of this mouse model to explore the potential link of TGIF to the defect in brain development, especially related to holoprosencephaly (HPE) disorder. HPE is a human genetic disease with characteristic defects in brain and craniofacial development. HPE is the most common structural defect of the developing forebrain in humans, and mutations have been found in genes that govern neural tube patterning in early brain development. TG-interacting factor (TGIF) is a homeobox protein that functions as a transcriptional co-repressor to modulate transforming growth factor beta (TGF-beta) induced gene transcription by direct association with Smad proteins. Mutations of TGIF have been found in HPE patients, indicating that TGIF may play an important role in forebrain development. Currently, the in vivo function of TGIF is unknown. In this proposal, we will employ the following two strategies to elucidate the biological function of TGIF in brain development: (1)We will characterize the biological function of TGIF by knockout of TGIF gene in mouse, then the effect of TGIF deficiency on the development of forebrain and craniofacial structures will be followed with regard to HPE phenotype. (2) Using this mouse model, we will study the potential mechanism underlying the function of TGIF in the development of forebrain structures. We will analyze the neural tube in which the neural tube patterning in TGIF-deficient mice. Taken together, the proposed studies in these two aspects will delineate the function of TGIF in mouse development, especially its implication in HPE pathogenesis.
| Chen, Qian; Chen, Hanying; Zheng, Dawei et al. (2009) Smad7 is required for the development and function of the heart. J Biol Chem 284:292-300 |
| Kuang, Chenzhong; Xiao, Yan; Yang, Ling et al. (2006) Intragenic deletion of Tgif causes defectsin brain development. Hum Mol Genet 15:3508-19 |
