了解神經(jīng)干細(xì)胞的分化過(guò)程和神經(jīng)前體細(xì)胞的命運(yùn)決定對(duì)于再生醫(yī)學(xué)領(lǐng)域有重要的意義。
在神經(jīng)系統(tǒng)發(fā)育的過(guò)程中,，神經(jīng)祖細(xì)胞既要維持自我更新,，又要分化成各種類型的神經(jīng)細(xì)胞，而這種分化與自我更新之間的平衡是依靠多種生長(zhǎng)因子協(xié)同作用來(lái)完成的,。例如,，在端腦，Shh(sonic hedgehog)途徑能夠啟動(dòng)神經(jīng)祖細(xì)胞的自我更新,、抑制終末分化,。與之相反的是，RA(retinoic acid,，維甲酸)能夠促進(jìn)分化,、抑制神經(jīng)祖細(xì)胞的增殖,。但是，這些生長(zhǎng)因子之間是如何協(xié)同合作,，使神經(jīng)系統(tǒng)正常發(fā)育的,，目前尚不清楚。
Nkx2.1是決定皮層中間神經(jīng)元亞型的轉(zhuǎn)錄因子,。它規(guī)定了內(nèi)側(cè)神經(jīng)嵴（MGE）中神經(jīng)母細(xì)胞的身份,。Nkx2.1低表達(dá)的細(xì)胞趨向于遷移到皮層，而Nkx2.1高表達(dá)的細(xì)胞則會(huì)遷移到紋狀體,。而Nkx2.1正是Shh途徑的一個(gè)靶蛋白,。
本文中，研究人員通過(guò)將胚胎干細(xì)胞誘導(dǎo)分化成神經(jīng)細(xì)胞來(lái)模擬正常的神經(jīng)系統(tǒng)發(fā)生過(guò)程,。發(fā)現(xiàn)了一種叫做Activin (激活素)的潛在神經(jīng)營(yíng)養(yǎng)因子,，在誘導(dǎo)神經(jīng)細(xì)胞分化中起著關(guān)鍵作用。Activin通過(guò)抑制Shh途徑和增強(qiáng)RA途徑使細(xì)胞退出有絲分裂周期,，進(jìn)入分化,。
此外，研究人員還發(fā)現(xiàn),，Activin 能夠通過(guò)Shh途徑來(lái)影響Nkx2.1的表達(dá),，從而決定了這些神經(jīng)前體細(xì)胞的遷移方向，以及它們會(huì)發(fā)育成哪種亞型的皮層中間神經(jīng)元,。（生物谷 Bioon.com ）
doi:10.1038/ncomms1817
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Activin induces cortical interneuron identity and differentiation in embryonic stem cell-derived telencephalic neural precursors
Serafí Cambray, Charles Arber, Graham Little, Antonios G. Dougalis, Vincenzo de Paola, Mark A. Ungless, Meng Li & Tristan A. Rodríguez
Understanding the mechanisms underlying neural progenitor differentiation and neuronal fate specification is critical for the use of embryonic stem cells (ESCs) for regenerative medicine. Cortical interneurons are of particular interest for cell transplantation; however, only a limited subset of these neurons can be generated from ESCs. Here we uncover a pivotal role for Activin in regulating the differentiation and identity of telencephalic neural precursors derived from mouse and human ESCs. We show that Activin directly inhibits the mitogenic sonic hedgehog pathway in a Gli3-dependent manner while enhancing retinoic acid signalling, the pro-neurogenic pathway. In addition, we demonstrate that Activin provides telencephalic neural precursors with positional cues that specifically promote the acquisition of a calretinin interneuron fate by controlling the expression of genes that regulate cortical interneuron identity. This work demonstrates a novel means for regulating neuronal differentiation and specification of subtype identity.
