REGULATION OF NEUROENDOCRINE SWITCHING EVENTS

描述（改编自申请人的摘要）：定义 神经内分泌系统中的特定基因 系统被激活，以及它们的表达是如何被调节的， 终末分化的细胞，是免疫学领域的中心问题。 内分泌学这项赠款的一个主要目标是确定细胞- 调节神经内分泌基因的特定策略， 特别是在下丘脑和各种神经嵴来源的 内分泌和非内分泌细胞类型， 表达调节肽。在上一个项目期间， 首席研究员发现并表征了几种新的POU 特异性下丘脑细胞表达的结构域转录因子 以促肾上腺皮质激素释放激素表达为特征的类型 (CRH)和表达降钙素基因的神经嵴衍生细胞类型 相关肽（CGRP）。这些转录因子可以作为 下丘脑和神经嵴发育的决定因素。在 这次竞争性的续约，重点是调查 这些假定的决定因素在激活中的发育作用 神经内分泌系统的特定基因，使用同源 在胚胎干细胞中进行重组，以产生每个 转录因子基因组位点。假设这些POU 结构域因子在CRH的激活中起着关键作用， 和CGRP转录单位，发挥作用，在个体发育，终端 细胞表型的分化和细胞活力。他们的角色将 在其他关键转录单位的激活中进行评估， 神经内分泌系统，包括加压素、催产素、GRH和物质 P.根据最初的数据，这些实验很可能在遗传学上 将新的转录因子与下丘脑的控制联系起来， 垂体轴和神经内分泌系统的调节基因。 实验将针对调查的基础上，选择 高度相关因子在靶基因激活中的作用， 这些POU结构域因子高度选择的分子机制 限制性二分DNA结合位点。这些实验将提供 对内分泌相关的发展策略的见解 下丘脑，在激活特定的调控基因，并在产生 神经内分泌系统中的成熟细胞类型。

DESCRIPTION (Adapted from the applicant's abstract): Defining the molecular mechanisms by which specific genes in the neuroendocrine system are activated, and how their expression is regulated in terminally differentiated cells, is a central problem in the field of endocrinology. A major goal under this grant has been to identify cell- specific strategies by which neuroendocrine genes are regulated, particularly in hypothalamus and in the diverse neural crest- derived endocrine and non-endocrine cell types in which genes encoding regulatory peptides are expressed. In the previous project period, the principal investigator discovered and characterized several novel POU domain transcription factors expressed in specific hypothalamic cell types characterized by expression of corticotropin-releasing hormone (CRH) and neural-crest derived cell types expressing calcitonin gene related peptides (CGRP). These transcription factors could serve as determining factors in hypothalamus and neural crest development. In this competitive renewal, focus is on the investigation of the developmental roles of these putative determining factors in activation of specific genes of the neuroendocrine system, using homologous recombination in embryonic stem cells to generate mice null for each transcription factor genomic locus. It is hypothesized that these POU domain factors serve critical functions both in activation of the CRH and CGRP transcription units, exerting roles during ontogeny, terminal differentiation of cell phenotypes, and cell viability. Their roles will be assessed in activation of other critical transcription units of the neuroendocrine system including vasopressin, oxytocin, GRH, and substance P. Based on initial data, these experiments are likely to genetically link the novel transcription factors to control of the hypothalamic- pituitary axis and regulatory genes of the neuroendocrine system. Experiments will be directed at investigating the basis for selective actions of highly related factors in target gene activation, and the molecular mechanisms by which these POU domain factors select highly restricted bipartite DNA binding sites. These experiments will provide insights into developmental strategies involved in the endocrine hypothalamus, in activating specific regulatory genes, and in generating mature cell types in the neuroendocrine system.