Ntf3 acts downstream of Sip1 in cortical postmitotic neurons to control progenitor cell fate through feedback signaling
Ntf3 acts downstream of Sip1 in cortical postmitotic neurons to control progenitor cell fate through feedback signaling
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DOI：
10.1242/dev.114173
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发表时间：
2014-09-01
期刊：
影响因子：
4.6
通讯作者：
Tarabykin, Victor
中科院分区：
文献类型：
--
作者：
Parthasarathy, Srinivas;Srivatsa, Swathi;Tarabykin, Victor
皮层祖细胞经历进行性命运限制，从而依次产生不同层次的新皮层。然而，这些祖先是如何精确地改变他们的命运的，仍然存在很大的争议。我们之前已经证明了皮层反馈机制的存在，其中有丝分裂后神经元向祖细胞发出信号，并促进从神经发生到胶质发生的转换。我们发现，Sip1 (Zeb2)，一种转录抑制因子，控制着这种反馈信号。类似的机制也被认为是控制神经元细胞类型的规范；然而，潜在的机制尚未确定。本研究提供的直接证据表明，在发育中的小鼠新皮层中，作为Sip1靶神经营养因子的Ntf3作为有丝分裂后神经元和祖细胞之间的反馈信号，促进了顶端祖细胞（AP）到基础祖细胞（BP）和深层细胞（DL）到上层细胞（UL）的命运转换。我们发现，新皮质神经元中特异性过表达Ntf3会以牺牲AP为代价促进BP的过度产生。这种转变随后是DL的减少和UL神经元产生的增加。相比之下，Ntf3的缺失会导致第六层神经元的增加，但不会挽救Sip1突变体的表型，这意味着其他平行通路也控制着祖细胞命运开关的时间。
Cortical progenitors undergo progressive fate restriction, thereby sequentially producing the different layers of the neocortex. However, how these progenitors precisely change their fate remains highly debatable. We have previously shown the existence of cortical feedback mechanisms wherein postmitotic neurons signal back to the progenitors and promote a switch from neurogenesis to gliogenesis. We showed that Sip1 (Zeb2), a transcriptional repressor, controls this feedback signaling. A similar mechanism was also suggested to control neuronal cell type specification; however, the underlying mechanism was not identified. Here, we provide direct evidence that in the developing mouse neocortex, Ntf3, a Sip1 target neurotrophin, acts as a feedback signal between postmitotic neurons and progenitors, promoting both apical progenitor (AP) to basal progenitor (BP) and deep layer (DL) to upper layer (UL) cell fate switches. We show that specific overexpression of Ntf3 in neocortical neurons promotes an overproduction of BP at the expense of AP. This shift is followed by a decrease in DL and an increase in UL neuronal production. Loss of Ntf3, by contrast, causes an increase in layer VI neurons but does not rescue the Sip1 mutant phenotype, implying that other parallel pathways also control the timing of progenitor cell fate switch.