Earmuff maintains restricted potentials of mature secondary neuroblasts

描述（由申请人提供）：限制成体干细胞谱系中转运扩增细胞增殖和抑制其去分化的机制尚不清楚。果蝇幼虫脑中成熟的次级成神经细胞类似于脊椎动物的运输放大细胞，并经历有限轮的不对称分裂以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耳套（Erm），它限制增殖和抑制成熟的次级神经母细胞的去分化。在突变的大脑中，成熟的次级神经母细胞去分化回到它们的亲本神经母细胞命运，导致II型神经母细胞的急剧增加。去分化成神经细胞的生理和功能特性与内源性II型成神经细胞是不可区分的。Erm突变体脑中的去分化表型可以通过Erm或其小鼠同源物在成熟的次级成神经细胞中的靶向表达来挽救。有趣的是，在突变的大脑中，成熟的次级神经母细胞的去分化独立于皮质细胞的极性发生。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，但通过负调节Notch信号来抑制去分化。我们的建议概述如下，将提供深入了解Erm限制增殖和抑制成熟的次级成神经细胞的去分化的分子机制。 公共卫生相关性：许多类型的干细胞在正常发育、维持稳态和组织再生期间产生瞬时扩增细胞以瞬时扩增未分化祖细胞库。限制转运扩增细胞的增殖和抑制去分化是产生必要的分化后代同时防止可能导致肿瘤发生的异常细胞命运特化的关键。因此，增殖和去分化是如何调节过境扩增细胞是一个基本的问题，几乎所有的成体干细胞类型的关注。在这个建议中，我们将使用成熟的次生神经母细胞在发展中的苍蝇幼虫的大脑作为一个在体内模型系统，研究如何增殖和去分化调节过境放大细胞。

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. PUBLIC HEALTH RELEVANCE: Many types of stem cells generate transit amplifying cells to transiently expand the pool of un- differentiated progenitors during normal development, maintenance of homeostasis and tissue regeneration. Restriction of proliferation and suppression of de-differentiation in transit amplifying cells are keys to generate necessary differentiated progeny while preventing aberrant cell fate specification that might lead to tumorigenesis. Thus, how proliferation and de-differentiation are regulated in transit amplifying cells is a fundamental question that concerns virtually all adult stem cell types. In this proposal, we will use mature secondary neuroblasts in developing fly larval brains as an in vivo model system to study how proliferation and de-differentiation are regulated in transit amplifying cells.