Hes-1 通过调节 Tlx3（HOX11L2）的表达来调控神经前体细胞的兴奋性命运。
Hes-1 regulates the excitatory fate of neural progenitors through modulation of Tlx3 (HOX11L2) expression.
机构信息
Neuro Stem Cell Biology Laboratory, Department of Neurobiology, Rajiv Gandhi Center for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram, Kerala, 695 014, India.
出版信息
Cell Mol Life Sci. 2012 Feb;69(4):611-27. doi: 10.1007/s00018-011-0765-8. Epub 2011 Jul 9.
Abstract
Tlx3 (HOX11L2) is regarded as one of the selector genes in excitatory versus inhibitory fate specification of neurons in distinct regions of the nervous system. Expression of Tlx3 in a post-mitotic immature neuron favors a glutamatergic over GABAergic fate. The factors that regulate Tlx3 have immense importance in the fate specification of glutamatergic neurons. Here, we have shown that Notch target gene, Hes-1, negatively regulates Tlx3 expression, resulting in decreased generation of glutamatergic neurons. Down-regulation of Hes-1 removed the inhibition on Tlx3 promoter, thus promoting glutamatergic differentiation. Promoter-protein interaction studies with truncated/mutated Hes-1 protein suggested that the co-repressor recruitment mediated through WRPW domain of Hes-1 has contributed to the repressive effect. Our results clearly demonstrate a new and unique role for canonical Notch signaling through Hes-1, in neurotransmitter/subtype fate specification of neurons in addition to its known functional role in proliferation/maintenance of neural progenitors.
摘要
TLX3（HOX11L2）被认为是神经系统不同区域兴奋性神经元与抑制性神经元命运特化的选择基因之一。TLX3 在有丝分裂后未成熟神经元中的表达有利于谷氨酸能神经元而不是 GABA 能神经元的命运。调节 TLX3 的因素在谷氨酸能神经元的命运特化中具有重要意义。在这里，我们已经表明，Notch 靶基因 Hes-1 负调控 TLX3 的表达，导致谷氨酸能神经元生成减少。Hes-1 的下调消除了对 TLX3 启动子的抑制，从而促进了谷氨酸能分化。与截短/突变 Hes-1 蛋白的启动子-蛋白相互作用研究表明，通过 Hes-1 的 WRPW 结构域介导的共抑制因子募集有助于抑制作用。我们的研究结果清楚地表明，经典 Notch 信号通过 Hes-1 在神经元神经递质/亚型命运特化中发挥了新的独特作用，除了其在神经祖细胞增殖/维持中的已知功能作用之外。
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