Jhas Sumit, Ciura Sorana, Belanger-Jasmin Stephanie, Dong Zhifeng, Llamosas Estelle, Theriault Francesca M, Joachim Kerline, Tang Yeman, Liu Lauren, Liu Jisheng, Stifani Stefano
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4.
J Neurosci. 2006 Oct 25;26(43):11061-71. doi: 10.1523/JNEUROSCI.1358-06.2006.
The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neurons. In contrast, a related Hes family member termed Hes6 promotes neurogenesis. It is shown here that knockdown of endogenous Hes6 causes supernumerary cortical progenitors to differentiate into cells that exhibit an astrocytic morphology and express the astrocyte marker protein GFAP. Conversely, exogenous Hes6 expression in cortical progenitors inhibits astrocyte differentiation. The negative effect of Hes6 on astrocyte differentiation is independent of its ability to promote neuronal differentiation. We also show that neither its proneuronal nor its anti-gliogenic functions appear to depend on Hes6 ability to bind to DNA via the basic arm of its bHLH domain. Both of these activities require Hes6 to be localized to nuclei, but only its anti-gliogenic function depends on two short peptides, LNHLL and WRPW, that are conserved in all Hes6 proteins. These findings suggest that Hes6 is an important regulator of the neurogenic phase of cortical development by promoting the neuronal fate while suppressing astrocyte differentiation. They suggest further that separate molecular mechanisms underlie the proneuronal and anti-gliogenic activities of Hes6 in cortical progenitor cells.
调节哺乳动物大脑皮质细胞多样性生成的机制正开始得到阐明。在这方面，毛状/分裂增强子（Hes）1和5是碱性螺旋-环-螺旋（bHLH）因子，可抑制多能皮质祖细胞向神经元分化。相比之下，一个相关的Hes家族成员Hes6则促进神经发生。本文表明，敲低内源性Hes6会使多余的皮质祖细胞分化为呈现星形胶质细胞形态并表达星形胶质细胞标志物蛋白GFAP的细胞。相反，在皮质祖细胞中过表达Hes6会抑制星形胶质细胞分化。Hes6对星形胶质细胞分化的负面影响与其促进神经元分化的能力无关。我们还表明，其促进神经元生成和抑制胶质生成的功能似乎均不依赖于Hes6通过其bHLH结构域的碱性臂与DNA结合的能力。这两种活性都要求Hes6定位于细胞核，但只有其抑制胶质生成的功能依赖于在所有Hes6蛋白中都保守的两个短肽LNHLL和WRPW。这些发现表明，Hes6通过促进神经元命运同时抑制星形胶质细胞分化，是皮质发育神经发生阶段的重要调节因子。它们进一步表明，Hes6在皮质祖细胞中的促进神经元生成和抑制胶质生成活性有着不同的分子机制。
