Sequential activation of transcriptional repressors promotes progenitor commitment by silencing stem cell identity genes.
Sequential activation of transcriptional repressors promotes progenitor commitment by silencing stem cell identity genes.
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作者：
Rives-Quinto N;Komori H;Ostgaard CM;Janssens DH;Kondo S;Dai Q;Moore AW;Lee CY
干细胞通过中间祖细胞间接产生分化细胞，驱动脊椎动物脑的进化。由于缺乏谱系信息，干细胞功能，包括产生中间祖细胞的能力，如何在祖细胞定型过程中消失仍不清楚。蝇幼虫脑中的II型神经母细胞不对称分裂以产生神经母细胞和致力于中间祖细胞（INP）身份的后代。我们确定无尾（Tll）作为II型神经母细胞功能特性的主要调节因子，包括产生INPs的能力。在INP定型过程中，转录抑制因子的连续表达通过Hdac3起作用以沉默tll。降低阻遏物活性允许重新激活INPs中的Notch以异位诱导tll表达，从而驱动额外的成神经细胞形成。敲低hdac3功能防止在INP承诺期间tll的下调。我们认为，干细胞身份基因的持续失活允许中间祖细胞在间接神经发生过程中稳定地产生多样化的分化细胞。
Stem cells that indirectly generate differentiated cells through intermediate progenitors drives vertebrate brain evolution. Due to a lack of lineage information, how stem cell functionality, including the competency to generate intermediate progenitors, becomes extinguished during progenitor commitment remains unclear. Type II neuroblasts in fly larval brains divide asymmetrically to generate a neuroblast and a progeny that commits to an intermediate progenitor (INP) identity. We identified Tailless (Tll) as a master regulator of type II neuroblast functional identity, including the competency to generate INPs. Successive expression of transcriptional repressors functions through Hdac3 to silence tll during INP commitment. Reducing repressor activity allows re-activation of Notch in INPs to ectopically induce tll expression driving supernumerary neuroblast formation. Knocking-down hdac3 function prevents downregulation of tll during INP commitment. We propose that continual inactivation of stem cell identity genes allows intermediate progenitors to stably commit to generating diverse differentiated cells during indirect neurogenesis.