Molecular mechanisms underlying cell-fate determination during organ development.

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，已知神经干细胞驻留在神经上皮中。研究表明，这三种细胞类型从神经干细胞分化是由细胞外部信号和细胞内在程序调控的。我们已经证明BMP2抑制神经元分化，BMP2诱导负调节螺旋-环-螺旋（HLH）蛋白如Hes5、Id1和Id3的表达，导致神经源性碱性HLH转录因子如神经原素的转录活性受到抑制。我们发现少突胶质细胞分化诱导转录因子Olig2抑制星形胶质细胞分化诱导转录因子STAT3的活性。结合另一个研究小组的报告，神经原素通过抑制复杂的星形细胞分化来抑制STAT3、Smad1和p300的更多表达，我们的研究结果表明，发育中的大脑中的细胞命运部分取决于转录激活信号之间的交叉抑制相互作用。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也被认为能抑制神经元分化。我们已经证明BMP2可以增强notch诱导的小鼠神经上皮细胞中Hes-5的转录激活。激活的Smad1促进了p300向含有Notch细胞内结构域的核蛋白复合体的募集，这被认为有助于bmip2介导的Notch诱导的Hes-5表达的增强。这些数据表明Notch信号和BMP信号之间存在一种新的功能合作。总之，转录调控信号之间的交叉调控相互作用对于发育中的中枢神经系统细胞命运的决定是重要的。少

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