Shh regulation and function in the developing forebrain

描述(由申请人提供)：本申请的主要目的是 阐明控制信号表达的分子事件 腹侧间脑和小带内的分子声波刺猬(Shh) 丘脑限制区(ZLI)。除了它所扮演的角色之外 整个神经管的腹侧模式，遗传学研究表明 ZLI中Shh对前后部(A/P)生长和形态的影响 间脑。在腹侧操纵Shh信号的能力 间脑和ZLI分别有助于分析其 在丘脑发育中的作用(S)。因此，此应用程序将重点放在 Shh在这两个间脑区的表达调控机制。 首先，在卵子和体外操作雏鸡前脑将被用来 定义Shh表达上游的组织信号源，并鉴定 候选分子。第二，调节Shh的分子事件 将研究雏鸡的表达，最初集中在两个角色上 外在感应信号、BMP2和Nodal。第三，增强剂元素 调节腹侧间脑和ZLI中Shh的表达 在鸡外植体和转基因小鼠中发现。最后，Shh在 ZLI成熟和间脑模式将在有条件的情况下进行分析 小鼠的基因敲除。 这些研究旨在确定Shh上游的一些步骤 在间脑中的表达，从而有助于分析 腹侧间脑和ZLI信号的个体贡献 间脑的区域化。成人丘脑，主要整合 大脑的中枢，起源于间脑。定义分子 因此，控制该结构的发展的步骤可以提供 对前脑神经元回路形成的洞察和 系统中可能导致神经系统疾病的故障。此外， 所需信号的精确组合的知识 大脑的特定部分可能提供对新设计的洞察 治疗策略。作为一个新的调查者，这些研究将成为 为未来的传统研究资助申请奠定基础。

DESCRIPTION (provided by applicant): The major goal of this application is to elucidate the molecular events that control the expression of the signaling molecule Sonic hedgehog (Shh) in the ventral diencephalon and within the zona limitans intrathalamica (zli). In addition to its well-characterized role in ventral patterning throughout the neural tube, genetic studies suggest that Shh in the zli influences antero-posterior (A/P) growth and patterning of the diencephalon. The ability to manipulate Shh signaling in the ventral diencephalon and zli individually would facilitate the analysis of their role(s) in thalamic development. This application will therefore focus on the mechanisms regulating Shh expression in these two diencephalic domains. First, in ovo and in vitro manipulations of chick forebrain will be used to define tissue sources of signals upstream of Shh expression and to identify candidate molecules. Second, the molecular events that regulate Shh expression will be examined in chick, initially focusing on the roles of two extrinsic inductive signals, BMP2 and Nodal. Third, enhancer elements regulating Shh expression in the ventral diencephalon and zli will be identified in chick explant and transgenic mice. Finally, the role of Shh in zli maturation and diencephalic patterning will be analyzed in conditional knockouts in mice. These studies are intended to identify some of the steps upstream of Shh expression in the diencephalon and thus facilitate the analysis of the individual contributions of signals from the ventral diencephalon and zli to regionalization of the diencephalon. The adult thalamus, the main integration center of the brain, is derived from the diencephalon. Defining the molecular steps that control the development of this structure may therefore provide insight into the formation of neuronal circuitry in the forebrain and the faults in the system that can lead to neurological disease. Furthermore, knowledge of the precise combination of signals required to specify a particular part of the brain may provide insights into the design of new treatment strategies. As a new investigator, these studies will serve as the basis for a traditional research grant application in the future.