A NOVEL GENETIC APPROACH FOR ELUCIDATING GLYCOPEPTIDE HORMONE FUNCTIONS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 糖肽激素信号通路在女性健康和生育能力中起重要作用，并且对于哺乳动物的正常生理控制至关重要。这些受体的配体包括促性腺激素、FSH和LH以及甲状腺调节剂TSH。改变这些配体或其同源受体活性的突变与严重的发育缺陷、生育能力受损和广泛的健康缺陷有关。尽管糖肽激素与细胞表面受体结合后的细胞内信号事件级联反应多年来一直是深入研究的主题，但关于其途径仍有许多未知之处。效应器、调节器和目标。引人注目的是，糖肽激素信号的系统功能和遗传分析尚未在任何模式生物中进行，尽管这些系统在阐明信号转导网络方面具有明显的优势。为了深入了解糖肽激素受体信号转导的发育功能和调控机制，我们对FSHR-1进行了研究。FSH/LH/TSH受体的祖先直系同源物。利用强大的遗传学方法，我们已经确定了85个基因，与FSHR-1协调控制胚胎和幼虫发育，生殖系性别决定，生殖细胞成熟和生长。基于广泛的先例，我们预计这些调控网络和生物功能中的许多将在高等生物中被保存。深入了解这些途径对于理解糖肽激素信号传导对人类健康、生殖和疾病的复杂影响至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The glycopeptide hormone signaling pathways play essential roles in female health and fertility and are critical for normal physiological control in mammals. Ligands for these receptors include the gonadotropins, FSH and LH, and the thyroid regulator TSH. Mutations that alter the activities of these ligands or their cognate receptors are associated with severe developmental defects, impaired fertility, and a wide range of health deficits. Although the cascade of intracellular signaling events that follows binding of the glycopeptide hormones to their cell surface receptors has been the subject of intensive investigations for many years, much remains unknown regarding the pathways? effectors, modulators, and targets. Strikingly, systematic functional and genetic analyses of glycopeptide hormone signaling have not yet been carried out in any model organism, despite the clear strengths of these systems in elucidating signal transduction networks. To gain insight into the developmental functions and regulatory mechanisms underlying glycopeptide hormone receptor signaling, we have undertaken studies of FSHR-1, the sole C. elegans ancestral ortholog of the FSH/LH/TSH receptor. Using a powerful genetic approach, we have identified 85 genes that act coordinately with FSHR-1 to control embryonic and larval development, germline sexual determination, germ cell maturation, and growth. Based on extensive precedent, we expect that many of these regulatory networks and biological functions will be conserved in higher organisms. Thorough knowledge of these pathways will be critical for understanding the complex effects of glycopeptide hormone signaling on human health, reproduction, and disease.