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刺猬（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，指导胚胎和成体组织的发育，影响细胞命运决定、增殖、分化和组织模式。突变引起的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导致癌症。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。哺乳动物的hh蛋白有三种，声波蛋白（shh）、印度蛋白（ihh）和沙漠蛋白（dhh），每种蛋白都通过smoothened受体（smo）传递信号。小鼠中hh通路成分的纯合无效突变导致胚胎死亡，因此不能确定hh在卵巢中的作用。支持本申请的数据表明，hh途径的主要组分在小鼠卵巢中表达。我们使用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。该R 03提案侧重于实验，以表征在小鼠中观察到的卵泡发育的最后阶段的缺陷，其中在卵巢中表达了改变的smo的显性活性形式。 据推测，hh信号正常促进卵泡的发展，因为他们从初级到排卵前阶段的增长。排卵前LH峰触发hh信号下降，这是卵泡细胞分化最后阶段发生所必需的。这种分化是卵丘扩张、排卵和黄体化所必需的。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，并指出hh信号是如何参与这一过程的。R 03试验项目将建立一个转基因小鼠模型，并开始测试机制假说，以促进我们对hh信号在卵巢发育中的作用的理解。卵泡的发育需要复杂的信号传导，这通常是由其他组织中的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，这通常由其他组织中的刺猬信号传导途径调节。彻底了解卵巢的发育途径对于促进提高或控制生育力的方法的发展，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.