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Molecular mechanisms of forebrain morphogenesis

前脑形态发生的分子机制

基本信息

批准号：
18590168
负责人：
ISHIBASHI Makoto
金额：
$ 2.57万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590168/
关键词：
diencephalon nuclei positional information signal regulation of gene expression cerebral cortex cell cycle layer formation 前脳形態形成 Fgf Sonic hedgehog Lhx

项目摘要

The aim of this research is to elucidate molecular mechanisms of forebrain (diencephalon and telencephalon) development. In the diencephalon, there are many different nuclei in distinct positions. How these positions are determined has not been understood. To clarify the mechanisms, we examined expression patterns of Lhx1and Lhx9 in the developing chick diencephalon. Dynamic expression patterns were observed at the patterning stages. Previous studies suggested that these genes play important roles in differentiation of diencephalic nuclei. The above results led us to examination of regulatory mechanisms of Lhx1/9 genes. We hypothesized that some molecules provide the tissue with positional information. Candidate molecules are Sonic hedgehog which is expressed in the ventral region and Wnt which is expressed in the dorsal region. Since Lhx1 is expressed mainly in the ventral region, Sonic hedgehog likely regulates Lhx1 expression. In fact, ectopic expression of Sonic hedgehog induced ectopic Lhx1 expression in the diencephalon. Similarly, Wnt from the dorsal region seemed to regulate Lhx9 expression. Overexpression of Wnt3a led to expansion of the Lhx9 expression domain. FGF15/19 is also expressed in the dorsal region. Overexpression of FGF15 up-regulated Lhx9 as well.To elucidate the roles of Sonic hedgehog in corticogenesis in the mouse cerebrum, we analyzed the dorsal telencephalon-specific knock-outs. These mutants showed abnormal cell cycle kinetics and survival of the neural stem/progenitor cells. Also, positions of differentiated neurons in the cerebral cortex were affected.

本研究旨在阐明前脑(间脑和端脑)发育的分子机制。在间脑中，许多不同的核团位于不同的位置。这些立场是如何确定的，目前还不清楚。为了阐明Lhx1和Lhx9的表达机制，我们研究了Lhx1和Lhx9在发育中的鸡间脑中的表达模式。在图案化阶段观察到动态表达模式。以往的研究表明，这些基因在间脑核团的分化过程中起着重要作用。上述结果使我们对Lhx1/9基因的调控机制进行了研究。我们假设某些分子为组织提供位置信息。候选分子包括在腹侧表达的Sonic hedgehog和在背侧表达的Wnt。由于Lhx1主要在腹侧区域表达，Sonic hedgehog可能调节Lhx1的表达。事实上，Sonic hedgehog的异位表达诱导了间脑中Lhx1的异位表达。类似地，来自背侧的Wnt似乎调节Lhx9的表达。Wnt3a的过表达导致了Lhx9表达结构域的扩展。FGF15/19在背侧也有表达。FGF15的过表达也上调了Lhx9的表达。为了阐明Sonic Hedgehog在小鼠大脑皮质生成中的作用，我们分析了背侧端脑特异的基因敲除。这些突变体表现出异常的细胞周期动力学和神经干/祖细胞的存活。此外，大脑皮层中分化的神经元的位置也受到影响。