Hedgehog Signaling in Photoreceptor Differentiation and Maintenance

摘要 Hedgehog(HH)蛋白家族在决定神经细胞命运中起着重要作用 以及维持成人神经干细胞的潜能。以前的研究和我们的初步结果 提示Sonic Hedgehog(Shh)促进视网膜祖细胞增殖并影响 早期出生的视网膜神经元的规格。然而，HH信号在哺乳动物中的确切功能 光感受器细胞的发育和存活还不是很清楚。拟议的研究将使用 用分子遗传学方法阐明HH信号在小鼠光感受器中的作用 开发和维护。主要的HH受体成分(Smo)将是 利用转基因小鼠品系和表达Cre的逆转录病毒进行Cre/loxP重组消除 重组酶。干扰HH信号对出生后祖细胞增殖和细胞命运的影响 承诺，以及对光感受器分化和形态发生的影响将用分子分析 标记物和电子显微镜。HH信号在光感受器维持和存活中的作用 将通过去除成熟视网膜中的Smo基因或Shh基因来表征，随后 功能和形态分析。拟议的研究结果将阐明 哺乳动物光感受器分化和存活的重要信号通路。此外， 这些研究将为光感受器退化和 为抗击视网膜疾病开发新疗法的机会。

Abstract The Hedgehog (Hh) family of proteins plays important roles in the determination of neuronal cell fates and the maintenance of adult neural stem cell potentials. Previous studies and our preliminary results indicate that Sonic hedgehog (Shh) promotes retinal progenitor cell proliferation and affects specification of early born retinal neurons. However, the precise function of Hh signaling in mammalian photoreceptor cell development and survival is not well understood. The proposed research will use molecular genetic approaches to elucidate the roles of Hh signaling during mouse photoreceptor development and maintenance. The essential Hh receptor component Smoothened (Smo) will be eliminated by Cre/loxP recombination using transgenic mouse lines and retroviruses expressing Cre recombinase. The effects of disrupting Hh signaling on postnatal progenitor proliferation and cell fate commitment, and on photoreceptor differentiation and morphogenesis will be analyzed using molecular markers and electron microscopy. The roles of Hh signaling in photoreceptor maintenance and survival will be characterized by ablating the Smo gene or the Shh gene in the mature retina followed by functional and morphological analyses. Results of the proposed research will elucidate the function of an important signaling pathway in mammalian photoreceptor differentiation and survival. Moreover, these studies will provide new insights into mechanisms of photoreceptor degeneration and opportunities to develop novel therapies for combating retinal diseases.