Identification of the molecule basis on Hes1 oscillation that contributes to the heterogeneous differentiation of stem cells.

胚胎干细胞在诱导分化时表现出异质性反应。我们已经证明Hes1在小鼠ES细胞中的表达是振荡的，并且这种振荡表达有助于异质性反应。我们发现以下三个结果得到了这笔赠款的支持。1.我们发现在ES细胞分化过程中，Hes1作为Notch信号的抑制因子而不是效应分子，并且持续表达Hes1通过抑制Notch信号促进了对中胚层的偏爱而不是神经的命运。2.我们发现Hes1缺失促进了人ES和iPS细胞系以及小鼠ES细胞系的神经分化。3.我们从小鼠ES细胞中与Hes1亲和纯化的蛋白中寻找新的Hes1振荡调节因子，发现去泛素酶通过去除Hes1中的泛素分子来稳定Hes1蛋白，调节Hes1振荡，并调节神经干细胞的神经元分化。

Embryonic stem (ES) cells display heterogeneous responses upon induction of differentiation. We have shown that Hes1 expression oscillates in mouse ES cells and that this oscillating expression contributes to the heterogeneous responses. We found the following three results supported by this grant. 1. We found that Hes1 acts as an inhibitor but not as an effector of Notch signaling in ES cell differentiation and that sustained Hes1 expression promotes the preference for the mesodermal rather than the neural fate by suppression of Notch signaling. 2. We found that Hes1 depletion enhances the neural differentiation in both human ES and iPS cell lines as well as mouse ES cell lines. 3. We searched new regulators of Hes1 oscillation from affinity-purified proteins with Hes1 from mouse ES cells and found that the deubiquitinases stabilize Hes1 protein via removing ubiquitin molecules from Hes1, modulate Hes1 oscillation and regulate the neuronal differentiation of neural stem cells.