Analysis of brain development in TGIF deficient mouse

描述(申请人提供)：这是一个R03应用程序，重点是TGIF基因敲除小鼠的初步特征，并使用这个小鼠模型来探索TGIF与大脑发育缺陷的潜在联系，特别是与完整前脑(HPE)障碍相关的缺陷。HPE是一种人类遗传性疾病，具有典型的脑和颅面发育缺陷。HPE是人类发育中的前脑最常见的结构缺陷，在大脑发育的早期，已经发现了控制神经管模式的基因突变。TG相互作用因子(TGIF)是一种同源盒蛋白，通过与Smad蛋白直接结合，发挥转录共抑制因子的作用，调节转化生长因子β(TGF-β)诱导的基因转录。在HPE患者中发现了TGIF的突变，提示TGIF可能在前脑发育中起重要作用。目前，TGIF在体内的功能尚不清楚。在本方案中，我们将采用以下两种策略来阐明TGIF在脑发育中的生物学功能：(1)我们将通过敲除TGIF基因来表征TGIF在小鼠脑发育中的生物学功能，然后从HPE表型的角度来观察TGIF缺陷对前脑和颅面结构发育的影响。(2)利用该小鼠模型，研究TGIF在前脑结构发育中的作用机制。我们将分析TGIF缺陷小鼠的神经管模式。综上所述，这两个方面的研究将阐明TGIF在小鼠发育中的作用，特别是它在HPE发病机制中的意义。

DESCRIPTION (provided by applicant): 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.