Homeodomain Repressor Msx1 in Gonadotrope Differentiation

描述（申请人提供）：垂体前叶的正常发育和功能对包括生长、代谢和生殖在内的多种生理过程至关重要。成熟的垂体前叶促性腺在生殖调节中作为激素信号整合的控制中心。促性腺激素的发育需要高度协调的转录程序，利用调节蛋白的协调活性来产生最终分化状态；然而促性腺激素成熟的机制仍有待充分阐明。本应用程序的目的是研究同源结构域抑制因子Msx1在促性腺激素分化和发育中的转录调控。Msx1表达的下降与谱系特异性垂体转录因子1GSU和GnRHR的表达开始一致。我的假设是Msx1通过抑制早期促性腺激素特异性基因（常见的1-亚基（1GSU）和GnRH受体（GnRHR））在早期垂体发育中起负调节作用，从而协调促性腺激素特异性基因程序的启动。目的1将在体外和体内研究Msx1在发育中的垂体1GSU和GnRHR抑制中的生理相关性。目的2将研究Msx1共阻遏子、分裂转导样增强子（TLE）蛋白的作用，Msx1对它们的募集，以及这些募集事件在促性腺激素分化过程中对1GSU和GnRHR抑制的作用。最后，Aim 3将通过表观遗传技术描述Msx1及其辅助因子在促性腺激素成熟中的功能。总的来说，通过利用我们创新的细胞谱系模型、基因组学和转基因小鼠，这些研究将为垂体发育的分子机制和促性腺激素特异性基因程序的开始提供新的见解。

DESCRIPTION (provided by applicant): Proper development and function of the anterior pituitary gland is critical for multiple physiological processes including growth, metabolism and reproduction. The mature anterior pituitary gonadotrope serves as a control center for the integration of hormonal signals in the regulation of reproduction. Gonadotrope development requires highly orchestrated transcriptional programs utilizing the coordinated activity of regulatory proteins to generate the terminally differentiated state; yet the mechanisms for gonadotrope maturation remain to be fully elucidated. The goal of this application is to investigate transcriptional regulation by homeodomain repressor Msx1 in gonadotrope differentiation and development. The decline of Msx1 expression coincides with the onset of expression of lineage-specific pituitary transcription factors 1GSU and GnRHR. My hypothesis is that Msx1 functions as a negative regulator in early pituitary development by repressing the early gonadotrope-specific genes: the common 1-subunit (1GSU) and GnRH receptor (GnRHR), thus coordinating the onset of the gonadotrope-specific gene program. Aim 1 will address the physiological relevance of Msx1 in 1GSU and GnRHR repression in the developing pituitary both in vitro and in vivo. Aim 2 will investigate the roles of Msx1 corepressors, the Transducin-Like Enhancer of split (TLE) proteins, their recruitment by Msx1, and the role of these recruitment events for 1GSU and GnRHR repression during gonadotrope differentiation. Finally, Aim 3 will delineate the functions of Msx1 and its cofactors in the maturation of the gonadotrope by epigenetic technologies. Overall, by utilizing our innovative cell lineage models, genomics, and genetically modified mice, these studies will provide novel insights into the molecular mechanisms of pituitary development and the onset of gonadotrope-specific gene programs. PUBLIC HEALTH RELEVANCE: Homeodomain transcription factors are crucial for pituitary organogenesis and cellular differentiation. The main goal of this proposal is to investigate the role of the homeodomain repressor Msx1 during pituitary development and the onset of gonadotrope-specific gene programs by utilizing an ensemble of differentiated pituitary cell models, in vivo genetics, molecular methods, and epigenetic approaches. This research will provide insight into novel regulatory mechanisms and significantly advance our understanding of gonadotrope differentiation and maturation.