Earmuff maintains restricted potentials of mature secondary neuroblasts

耳罩维持成熟次级神经母细胞的受限潜力

• 批准号: 7863320
• 负责人: Cheng-Yu Lee
• 金额: $ 29.66万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7863320
• 关键词: Back; Biological Models; Brain; Cell Cycle; Cell Lineage; Cell Polarity; Cell division; Cells; Data; Daughter; Development; Drosophila genus; Earmuff; Ectopic Expression; Ganglia; Gene Targeting; Genetic Models; Genetic Transcription; Homeostasis; Homologous Gene; Lead; Maintenance; Malignant Neoplasms; Mediating; Molecular; Mothers; Mus; Mutate; Myxoid cyst; Natural regeneration; Neurons; Nuclear; Phenotype; Physiological; Property; Repressor Proteins; Risk; Signal Transduction; Stem cells; Testing; Tissues; Transcription Repressor/Corepressor; adult stem cell; cell fate specification; cell type; fly; in vivo; in vivo Model; insight; mutant; neuroblast; notch protein; novel; prevent; progenitor; public health relevance; self-renewal; tissue regeneration; transcription factor; tumorigenesis

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.

描述（由申请人提供）：成体干细胞谱系中限制增殖和抑制转运扩增细胞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放大细胞，并经历有限轮次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罩（Erm），它限制增殖并抑制成熟次级神经母细胞的去分化。在 erm 突变大脑中，成熟的次级神经母细胞去分化回到其亲代神经母细胞命运，导致 II 型神经母细胞急剧增加。去分化的神经母细胞的生理和功能特性与内源性II型神经母细胞没有区别。 erm 突变大脑中的去分化表型可以通过在成熟的次级神经母细胞中靶向表达 Erm 或其小鼠同源物来挽救。有趣的是，erm 突变大脑中成熟次级神经母细胞的去分化发生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 信号传导来抑制去分化。下面概述的我们的建议将深入了解 Erm 限制增殖和抑制成熟次级神经母细胞去分化的分子机制。 公共健康相关性：许多类型的干细胞产生转运扩增细胞，以在正常发育、维持体内平衡和组织再生过程中暂时扩大未分化祖细胞库。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的关键，同时防止可能导致肿瘤发生的异常细胞命运规范。因此，如何调节转运扩增细胞的增殖和去分化是几乎所有成体干细胞类型的基本问题。在本提案中，我们将使用发育中的果蝇幼虫大脑中的成熟次级神经母细胞作为体内模型系统来研究转运放大细胞中如何调节增殖和去分化。