Analysis of Sonic hedgehog function during gonadogenesis

关于哺乳动物性腺形成的分子途径，人们知之甚少。人类性腺发育缺陷可能导致不育或性逆转，因此了解指导这一发育过程的机制是很重要的。Sonic hedgehog(Shh)是一种分泌型信号蛋白，参与脊椎动物和无脊椎动物多种组织的构型和轴的形成。缺乏功能性Shh基因产物的小鼠表现出许多缺陷，包括四肢、轴向骨骼和神经系统的异常发育。初步分析已经确定Shh突变小鼠的性腺生成也受到影响。与对照相比，Shh缺失胚胎的性腺变小，这种表型在雌性胚胎中尤为严重。此外，雄性和雌性的生殖道都不能正常形成。我们提出了三个主要的特定目标来确定Shh在小鼠性腺发生中的作用。首先，将确定Shh及其受体在发育中的性腺和周围中胚层中的表达模式。其次，将描述Shh-/-胚胎的性腺形成缺陷和突变表型的时间发育。最后，将进行实验，以确定Shh信号是否直接作用于发育中的性腺细胞，或者Shh是否参与了性腺产生的中脑肾的发育。

Relatively little is known about the molecular pathways that direct gonad formation in mammals. Defective gonadogenesis in humans can result in sterility or sex reversal, so it is important to understand the mechanisms that guide this developmental process. Sonic hedgehog (Shh) is a secreted signaling protein involved in the patterning and axis formation of many tissues in vertebrate and invertebrate species. Mice lacking a functional Shh gene product display a number of defects, including abnormal development of the limbs, axial skeleton and nervous system. A preliminary analysis has determined that gonadogenesis is also affected in Shh mutant mice. Gonads of Shh null embryos are reduced in size compared to controls and this phenotype is particularly severe in female embryos. In addition, the reproductive tracts of both males and females do not form properly. Three major specific aims are proposed to determine the roles of Shh in murine gonadogenesis. First, the expression pattern of Shh and its receptors in the developing gonad and the surrounding mesoderm will be determined. Second, the defects in gonad formation in the Shh -/- embryos and the temporal development of the mutant phenotype will be characterized. Finally, experiments will be performed to determine if Shh signals act directly on cells of the developing gonad or if Shh is involved in the development of the mesonephros, from which the gonad arises.