The Role of the Hedgehog Signaling Pathway in Ovarian Follicle Development

描述（由申请人提供）：拟议研究的目的是确定通过hedgehog （hh）通路的信号传导如何调节哺乳动物卵巢的发育。hh蛋白是一个分泌蛋白家族，指导胚胎和成人组织的发育，影响细胞命运的决定、增殖、分化和组织的模式。突变诱导的hh信号的增加在许多hh对正常发育至关重要的相同组织中引起癌症。Hh信号是果蝇卵泡发育所必需的，但其在哺乳动物卵巢中的作用尚不清楚。哺乳动物有三种hh蛋白，sonic (shh), indian （ihh）和desert (dhh)，它们都通过受体smoothened （smo）发出信号。小鼠hh通路组分的纯合零突变导致胚胎死亡，因此不能确定hh在卵巢中的作用。支持这一应用的数据表明，hh通路的主要成分在小鼠卵巢中表达。我们利用cre/lox技术有条件地删除或激活小鼠卵巢中的smo，以确定hh信号在体内的作用。这个R03提案的重点是通过实验来描述在小鼠卵泡发育的最后阶段观察到的一种缺陷，在这种缺陷中，smo的一种改变的显性活性形式在卵巢中表达。据推测，hh信号通常促进卵泡的发育，因为它们从初级阶段生长到排卵前阶段。排卵前的LH激增触发hh信号的下降，这对于卵泡细胞分化的最后阶段是必不可少的。这种分化是积云扩张、排卵和黄体形成所必需的。将卵巢中显性活性smo表达的小鼠与基因型匹配的对照小鼠进行比较，将确定排卵前卵泡发育最后阶段所必需的基因通路，并表明hh信号如何参与这一过程。这个R03试点项目将建立一个转基因小鼠模型，并开始测试机制假设，以促进我们对hh信号在卵巢发育中的作用的理解。卵泡发育需要复杂的信号传导，通常由其他组织中的hh通路调节。彻底了解卵巢的发育途径对于促进提高或控制生育能力的方法的发展，确定疾病的原因和开发治疗方法至关重要。卵泡发育需要复杂的信号传导，通常由其他组织中的刺猬信号通路调节。彻底了解卵巢的发育途径对于促进提高或控制生育能力的方法的发展，确定疾病的原因和开发治疗方法至关重要。

DESCRIPTION (provided by applicant): The objective of the proposed research is to determine how signaling through the hedgehog (hh) pathway regulates development in the mammalian ovary. The hh proteins are a family of secreted proteins that direct development in the embryo and in adult tissues, influencing cell fate determination, proliferation, differentiation and patterning of tissues. Mutation-induced increases in hh signaling cause cancer in many of the same tissues in which hh is critical for normal development. Hh signaling is required for ovarian follicle development in Drosophila but its role in the mammalian ovary is not known. There are three mammalian hh proteins, sonic (shh), indian (ihh) and desert (dhh), and each of them signals through the receptor smoothened (smo). Homozygous null mutations of hh pathway components in mice cause embryonic mortality and, consequently, fail to define the role of hh in the ovary. Data in support of this application show that major components of the hh pathway are expressed in the mouse ovary. We have used cre/lox technology to conditionally delete or to activate smo in the mouse ovary in order to determine the role of hh signaling in vivo. This R03 proposal focuses on experiments to characterize a defect in the final stages of follicle development observed in mice in which an altered, dominant active form of smo is expressed in the ovary. It is hypothesized that hh signaling normally promotes the development of follicles as they grow from the primary to the preovulatory stage. The preovulatory LH surge then triggers a decline in hh signaling which is essential to allow the final stages of follicle cell differentiation to occur. This differentiation is necessary for cumulus expansion, ovulation and luteinization. Comparison of mice in which dominant active smo is expressed in the ovary to genotype-matched control mice will identify gene pathways essential for the final stages of preovulatory follicle development and indicate how hh signaling is involved in this process. This R03 pilot project will establish a transgenic mouse model and begin to test mechanistic hypotheses to promote our understanding of the role of hh signaling in ovarian development. Follicle development requires complex signaling, which is often regulated by the hh pathway in other tissues. A thorough understanding of developmental pathways in the ovary is essential to promote development of methods to enhance or control fertility, to determine the causes of disease and to develop treatments. Follicle development requires complex signaling, which is often regulated by the hedgehog signaling pathway in other tissues. A thorough understanding of developmental pathways in the ovary is essential to promote development of methods to enhance or control fertility, to determine the causes of disease and to develop treatments.