Molecular Control of Shh/Gli Signalling in the Vertebrate CNS

0131264迈克尔·马蒂斯现代生物学面临的最大挑战之一是了解复杂的多细胞生物体（如人类）是如何从单细胞（受精卵）发育而来的。 这一个卵子，受精卵，实际上具有无限的潜力，可以产生成年哺乳动物中发现的所有数百万种不同的细胞类型。 然而，在发育过程中，随着细胞分裂和生长使成体生物体中的细胞彼此分化，细胞的潜力变得越来越受到限制。 在胚胎发育过程中区分细胞的一个重要机制涉及分泌的信号分子，这些信号分子提供空间信息，这对于确定它们的位置以及它们在成熟生物体中的特定功能或命运至关重要。 一种这样的信号分子被称为Sonic Hedgehog。 Sonic Hedgehog激活了接收到这种信号的细胞中的级联反应。 一个家族的基因，有一个核心作用，在解释声波刺猬提供的位置信息被称为Gli基因。 对果蝇的研究为Gli家族蛋白抑制Sonic Hedgehog信号的机制提供了重要的见解。 此外，Sonic Hedgehog和下游基因（包括Gli）的突变最近与癌症有关。该提案旨在利用小鼠遗传学来探索Gli基因在中枢神经系统发育中的功能。提出的一些实验的目的是测试是否方面的Gli蛋白在果蝇中开发的Sonic Hedgehog信号的作用模型适用于哺乳动物。 通过解决有关这一途径的调节的基本问题，将获得对中枢神经系统发育的更好理解。 这些见解也将为我们理解涉及Sonic Hedgehog和Gli基因异常的癌症机制提供有价值的见解。

0131264Michael P. MatiseOne of the greatest challenges to modern biology is to understand how complex, multi-cellular organisms such as humans develop from a single cell, the fertilized egg. This single egg, the zygote, has virtually unlimited potential to generate all the millions of different cell types that are found in an adult mammal. However, during development, the potential of cells becomes increasingly restricted as cell division and growth differentiate cells from one another in the adult organism. One important mechanism that appears to distinguish cells from one another during embryonic development involves secreted signalling molecules that provide spatial information which is critical for establishing their position and hence their specific function or fate in the mature organism. One such signalling molecule is known as Sonic Hedgehog. Sonic Hedgehog activates a cascade of responses in cells that receive this signal. A family of genes that have a central role in interpreting Sonic Hedgehog-supplied positional information are known as Gli genes. Studies in the fruitfly have provided important insights into the mechanisms by which Gli family proteins transduce the Sonic Hedgehog signal. In addition, mutations in Sonic Hedgehog and downstream genes, including Gli, have recently been implicated in cancers. This proposal seeks to utilize mouse genetics in order to explore the function of Gli genes in the development of the central nervous system. Some of the experiments proposed are designed to test whether aspects of the model for the role of Gli proteins in Sonic Hedgehog signalling developed in fruitflies are applicable to mammals. By addressing basic issues relating to the regulation of this pathway, a greater understanding of the development of the central nervous system will be gained. These insights will also provide valuable insights to our understanding of the mechanisms of cancers that involve Sonic Hedgehog and Gli gene abnormalities.