TEAD promotes lineage progression of subpallial neural progenitor cells independent of YAP/TAZ

The embryonic ventral telencephalon (subpallium) gives rise to extremely diverse types of cells. Although it is known that subpallial neural progenitors possess characteristics distinct from their cortical counterparts, the mechanisms governing their lineage progression are poorly understood. Here we show that TEAD, the key DNA-binding factor of the Hippo pathway, promotes lineage progression of subpallial neural progenitors; the loss of TEAD1 and TEAD2 (TEAD1/2) during mammalian brain development expands early progenitors and reduces late progenitors uniquely in the subpallium, but not in the cortex. Importantly, this function of TEAD1/2 is independent of their canonical partners in the Hippo pathway, transcriptional coactivators YAP and TAZ (YAP/TAZ), as the loss of YAP/TAZ leads to the opposite phenotypea depletion of early progenitors and increase in late progenitors. We further show that TEAD1/2 act at least in part by inhibiting Notch signaling and by cooperating with INSM1. It has been shown that orthologs of TEAD and INSM1 cooperate to regulate neuronal cell fate decisions in worms and flies. Our study reveals a remarkable evolutionary conservation of the function of this transcription factor complex during metazoan neural development. The MGEs from wild-type mice at E12.5 and E15.5, as well as Tead1/2 and Yap/Taz knockout mutant mice and appropriate controls at E14.5, were collected for scRNASeq analysis胚胎腹侧端脑（亚端脑，subpallium）可产生极为多样的细胞类群。尽管已有研究证实亚端脑神经前体细胞具备与其皮层同源细胞截然不同的特征，但调控其谱系进展的分子机制仍有待阐明。本研究发现，作为Hippo信号通路关键DNA结合因子的TEAD转录因子，可促进亚端脑神经前体细胞的谱系进展；在哺乳动物脑发育进程中敲除TEAD1与TEAD2（TEAD1/2），会特异性在亚端脑内扩增早期前体细胞并减少晚期前体细胞，而皮层区域未出现此类变化。值得注意的是，TEAD1/2的这一功能并不依赖于其在Hippo通路中的经典伴侣——转录共激活因子YAP与TAZ（YAP/TAZ），因为敲除YAP/TAZ会引发相反表型：早期前体细胞耗竭且晚期前体细胞数量增加。我们进一步证实，TEAD1/2至少部分通过抑制Notch信号通路，并与INSM1协同发挥调控作用。已有研究表明，TEAD与INSM1的同源物可协同调控线虫与果蝇的神经元细胞命运决定事件。本研究揭示了这一转录因子复合物在多细胞动物神经发育过程中的功能具备显著的进化保守性。本研究收集了胚胎日12.5（E12.5）与胚胎日15.5（E15.5）野生型小鼠的内侧神经节隆起（MGEs），以及胚胎日14.5（E14.5）时的Tead1/2与Yap/Taz基因敲除突变小鼠和相应对照组的样本，用于单细胞RNA测序（scRNASeq）分析。