Analysis of Sonic hedgehog function during gonadogenesis

相对而言，我们对哺乳动物生殖腺形成的分子途径知之甚少。人类促性腺功能缺陷可导致不育或性逆转，因此了解指导这一发育过程的机制非常重要。Sonic hedgehog （Shh）是一种分泌性信号蛋白，参与许多脊椎动物和无脊椎动物组织的模式和轴的形成。缺乏功能性Shh基因产物的小鼠表现出许多缺陷，包括四肢、轴骨和神经系统的异常发育。初步分析表明，Shh突变小鼠的促性腺功能也受到影响。与对照组相比，Shh缺失胚胎的性腺体积减小，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具体目标来确定Shh在小鼠促性腺激素生成中的作用。首先，确定Shh及其受体在发育性腺和周围中胚层中的表达模式。其次，将对Shh -/-胚中性腺形成的缺陷和突变表型的时间发育进行表征。最后，将进行实验来确定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.