Earmuff maintains restricted potentials of mature secondary neuroblasts

描述（由申请人提供）：成体干细胞谱系中限制转运扩增细胞增殖和抑制去分化的机制尚不清楚。果蝇幼虫大脑中成熟的次级神经母细胞类似于脊椎动物的转运扩增细胞，并经历有限轮的不对称分裂来再生并产生终末分化的神经元。我们发现了一种新的转录因子Earmuff (Erm)，它可以限制成熟的继发性神经母细胞的增殖和抑制去分化。在erm突变的大脑中，成熟的继发性神经母细胞分化回其亲代神经母细胞命运，导致II型神经母细胞急剧增加。去分化神经母细胞的生理和功能特性与内源性II型神经母细胞难以区分。通过在成熟的继发性神经母细胞中靶向表达erm或其小鼠同源物，可以挽救erm突变脑的去分化表型。有趣的是，在erm突变的大脑中，成熟的继发性神经母细胞的去分化与皮质细胞极性无关。我们的数据表明，Erm通过促进prospero介导的细胞周期退出来限制增殖，但通过负向调节Notch信号来抑制去分化。我们下面概述的建议将提供Erm限制增殖和抑制成熟继发性神经母细胞去分化的分子机制。

DESCRIPTION (provided by applicant): The mechanisms that restrict proliferation and suppress de-differentiation of transit amplifying cells in adult stem cell lineages are unknown. Mature secondary neuroblasts in Drosophila larval brains resemble vertebrate transit amplifying cells, and undergo limited rounds of asymmetric divisions to regenerate and to produce terminally differentiated neurons. We identified a novel transcription factor Earmuff (Erm), which restricts proliferation and suppresses de-differentiation of mature secondary neuroblasts. In erm mutant brains, mature secondary neuroblasts de-differentiate back into their parental neuroblast fates resulting in a dramatic increase in type II neuroblasts. The physiological and functional properties of the de-differentiated neuroblasts are indistinguishable from the endogenous type II neuroblasts. The de-differentiation phenotype in erm mutant brains can be rescued by targeted expression of Erm or its mouse homologs in mature secondary neuroblasts. Intriguingly, de-differentiation of mature secondary neuroblasts in erm mutant brains occurs independently of cortical cell polarity. Our data suggest that Erm restricts proliferation by promoting Prospero-mediate cell cycle exit, but suppresses de-differentiation by negatively regulating Notch signaling. Our proposal outlined below will provide insight into the molecular mechanisms by which Erm restricts proliferation and suppresses de-differentiation of mature secondary neuroblasts.