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Molecular mechanisms underlying cell-fate determination during organ development.

器官发育过程中细胞命运决定的分子机制。

基本信息

批准号：
14380337
负责人：
TAGA Tetsuya
金额：
$ 10.94万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Neurons, astrocytes, and oligodendrocytes, i.e., the three major cell types in the brain, differentiate from neural stem cells during development. In the developing brain, neural stem cells are known to reside in the neuroepithelium. It has been suggested that differentiation of these three cell types from the neural stem cells is regulated by cell-external cues as well as cell-intrinsic programs. We have shown that BMP2 inhibits neuronal differentiation and that BMP2 induces expression of negative regulatory helix-loop-helix (HLH) proteins such as Hes5, Id1 and Id3, leading to inhibition of transcriptional activity of neurogenic basic-HLH transcription factors such as neurogenin. We have found that an oligodendrocytic differentiation-inducing transcription factor, Olig2, inhibits the activity of an astrocytic differentiation-inducing transcription factor, STAT3. Taken together with a report by another group that neurogenin inhibits astrocytic differentiation by inhibiting complex form … More ation of STAT3, Smad1 and p300, our findings suggest that the cell-fate in the developing brain is determined in part by cross-inhibitory interactions among transcriptional activation signals. In the fate determination of mouse neuroepithelial cells, Notch signaling plays a role in keeping the progenitors from differentiating into neurons. BMP is also known to inhibit neuronal differentiation. We have shown that BMP2 enhances Notch-induced transcriptional activation of Hes-5 in mouse neuroepithelial cells. Recruitment of p300 to the nuclear protein complex containing the intracellular domain of Notch was facilitated by activated Smad1, which is suggested to contribute to BMIP2-mediated enhancement of Notch-induced Hes-5 expression. These data suggest a novel functional cooperation between Notch signaling and BMP signaling. In conclusion, cross-regulatory interactions among transcriptional regulatory signals are important for the cell-fate determination in the developing central nervous system. Less

神经元、星形胶质细胞和少突胶质细胞，即，大脑中的三种主要细胞类型在发育过程中从神经干细胞分化而来。在发育中的大脑中，已知神经干细胞存在于神经上皮中。这三种类型的神经干细胞的分化受到细胞外部信号和细胞内部程序的调控。我们已经表明，BMP 2抑制神经元分化，BMP 2诱导负调节螺旋-环-螺旋（HLH）蛋白，如Hes 5，Id 1和Id 3的表达，导致抑制神经原性碱性HLH转录因子，如neurogenin的转录活性。我们已经发现，少突分化诱导转录因子Olig 2抑制星形胶质细胞分化诱导转录因子STAT 3的活性。结合另一个研究小组的报告，神经素通过抑制复合物形式抑制星形胶质细胞分化， ...更多信息 STAT 3，Smad 1和p300的表达，我们的研究结果表明，在发育中的大脑细胞的命运是由转录激活信号之间的交叉抑制相互作用的一部分。在小鼠神经上皮细胞的命运决定中，Notch信号在阻止祖细胞分化为神经元中起作用。BMP还已知抑制神经元分化。我们已经表明，BMP 2增强Notch诱导的小鼠神经上皮细胞中Hes-5的转录激活。激活的Smad 1促进了p300向含有Notch细胞内结构域的核蛋白复合物的募集，这表明这有助于BMIP 2介导的Notch诱导的Hes-5表达的增强。这些数据表明Notch信号传导和BMP信号传导之间的新的功能合作。总之，转录调控信号之间的交叉调控相互作用是重要的细胞命运的决定在发展中的中枢神经系统。少