Hoxb1 controls cell fate specification and proliferative capacity of neural stem and progenitor cells
Hoxb1 controls cell fate specification and proliferative capacity of neural stem and progenitor cells
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DOI：
10.1634/stemcells.2008-0182
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发表时间：
2008-08-01
期刊：
影响因子：
5.2
通讯作者：
Gavalas, Anthony
中科院分区：
文献类型：
--
作者：
Gouti, Mina;Gavalas, Anthony
将胚胎干细胞（ESC）定向分化为具有特定身份的神经干细胞（NSC）和鉴定可介导NSC扩增的内源性途径是治疗（神经系统的变性疾病和创伤）的基本目标。我们报告说，及时诱导L 'SC衍生的神经干细胞的Hoxb 1转基因导致通过激活菱体4特异性遗传程序和抑制前神经身份的神经干细胞朝后脑特异性身份的规范。这种变化伴随着信号通路的变化，即神经系统的背腹（DV）轴的模式和伴随的DV神经祖细胞标志物表达的变化。此外，Hoxb 1介导的维持和扩增的后神经祖细胞。Hoxb 1（+）细胞在有丝分裂原撤除后继续增殖，并成为瞬时扩增的祖细胞，而不是终末分化。这部分归因于Notch信号通路的Hoxb 1依赖性激活和Notch依赖性STAT 3在Ser 727处的磷酸化，从而将Hox基因功能与维持活性Notch信号通路和JAK/STAT通路联系起来。因此，及时表达特定的Hox基因可以用来建立不同的后验身份的神经干细胞和神经祖细胞。ESC衍生的NSC具有受Hox基因调控的混合DV身份。最后，这些发现为阐明参与后部NSC和神经祖细胞扩增的分子途径奠定了基础。
The directed differentiation of embryonic stem cells (ESCs) into neural stem cells (NSCs) of specific identities and the identification of endogenous pathways that may mediate expansion of NSCs are fundamental goals for the treatment (of degenerative disorders and trauma of the nervous system. We report that timely induction of a Hoxb1 transgene in L'SC-derived NSCs resulted in the specification of NSCs toward a hindbrain-specific identity through the activation of a rhombomere 4-specific genetic program and the repression of anterior neural identity. This change was accompanied by changes in signaling pathways; that pattern the dorsoventral (DV) axis of the nervous system and concomitant changes in the expression of DV neural progenitor markers. Furthermore, Hoxb1 mediated the maintenance and expansion of posterior neural progenitor cells. Hoxb1(+) cells kept proliferating upon mitogen withdrawal and became transiently amplifying progenitors instead of terminally differentiating. This was partially attributed to Hoxb1-dependent activation of the Notch signaling pathway and Notch-dependent STAT3 phosphorylation at Ser 727, thus linking Hox gene function with maintenance of active Notch signaling and the JAK/STAT pathway. Thus, timely expression of specific Hox genes could be used to establish NSCs and neural progenitors of distinct posterior identities. ESC-derived NSCs have a mixed DV identity that is subject to regulation by Hox genes. Finally, these findings set the stage for the elucidation of molecular pathways involved in the expansion of posterior NSCs and neural progenitors.