Homeodomain Repressor Msx1 in Gonadotrope Differentiation

促性腺素分化中的同源域抑制子 Msx1

• 批准号: 8201570
• 负责人: HUIMIN XIE
• 金额: $ 4.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2013-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201570
• 关键词: Address; Anterior Pituitary Gland; Antibodies; Biological Assay; Cell Line; Cell Lineage; Cell model; Chromatin Structure; Complex; DNA Binding; DNA Polymerase II; Data; Development; Dlx protein; EMSA; Elements; Enhancers; Epigenetic Process; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Goals; Gonadotrope Cell; Gonadotropin-Releasing Hormone Receptor; Growth; Histones; Hormonal; In Vitro; Knockout Mice; Mediating; Messenger RNA; Metabolism; Methods; Modeling; Molecular; Molecular Genetics; Mus; Neurons; Organogenesis; Physiological; Physiological Processes; Pituitary Gland; Proteins; RNA; Receptor Gene; Recruitment Activity; Regulation; Repression; Reproduction; Research; Role; Signal Transduction; Small Interfering RNA; Staging; Technology; Testing; Time; Tissues; Transcript; Transcriptional Regulation; Transducin; cofactor; genetic regulatory protein; histone modification; homeodomain; in vitro Model; in vivo; innovation; insight; knock-down; novel; pituitary gland development; programs; promoter; receptor expression; transcription factor

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.

描述（由申请人提供）：垂体前叶的正常发育和功能对于包括生长、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激素作为一个控制中心，整合激素信号调节生殖。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终末分化状态，但促性腺激素成熟的机制仍有待充分阐明。本申请的目的是研究同源结构域阻遏蛋白Msx 1在促性腺细胞分化和发育中的转录调控。Msx 1表达的下降与谱系特异性垂体转录因子1GSU和GnRHR表达的开始一致。我的假设是Msx 1通过抑制早期促性腺激素特异性基因：共同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将解决的生理相关性Msx 1在1GSU和GnRHR抑制在发育中的垂体在体外和体内。目的2将探讨Msx 1辅阻遏物的作用，分裂的转导蛋白样增强子（TLE）蛋白，他们的招聘Msx 1，和这些招聘事件的作用1GSU和GnRHR抑制在促性腺细胞分化。最后，目标3将描绘Msx 1和它的辅因子在促性腺激素成熟的表观遗传技术的功能。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启动提供新的见解。 公共卫生相关性：同源结构域转录因子对垂体器官发生和细胞分化至关重要。这项建议的主要目标是调查的同源结构域阻遏蛋白Msx 1在垂体发育和促性腺激素特异性基因程序的发病过程中的作用，通过利用分化的垂体细胞模型，体内遗传学，分子方法和表观遗传学方法的合奏。这项研究将提供深入了解新的调控机制，并显着推进我们对促性腺细胞分化和成熟的理解。