Molecular mechanism of CNS regeneration in Drosophila

果蝇中枢神经系统再生的分子机制

• 批准号: 1790826
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1790826
• 关键词: Molecular; mechanism; CNS; regeneration; Drosophila

The aim is to investigate the molecular mechanisms of central nervous system (CNS) regeneration, using the fruit-fly Drosophila as model organism. The CNS does not regenerate upon injury, leading to permanent disability, but damage and disease to the brain or spinal cord induce a limited regenerative response in glial cells, which if understood, could be harnessed to promote regeneration and repair. Glial cells of ensheathing cell lineages (which enwrap axons), divide, produce trophic factors that maintain neuronal survival, aid axonal re-growth and navigation, and re-enwrap axons, leading to limited recovery of behaviour. This response is evolutionarily conserved, from insects to humans, revealing an underlying a genetic mechanism. Understanding this mechanism is essential to control the proliferation and differentiation of stem and progenitor cells for therapeutic activation in vivo, and for cell transplantations. Funded by BBSRC, the team of Dr Hidalgo discovered a gene network underlying the glial regenerative response. It involves the genes Notch and prospero (pros), and pros and NFkB, that together prime cells to respond to injury, enable a fast response and up-regulate the expression of kon-tiki (kon). And negative feedback that switches off kon, restores homeostasis and terminates the response to injury. Kon activates glial proliferation and differentiation onset, thus enabling glial regeneration; Pros inhibits proliferation, restoring homeostasis, and activates and maintains glial differentiation. In collaboration with mammalian experts, the Hidalgo team showed that this gene network is evolutionarily conserved in the mouse. Still, how glial cells interact with neurons in response to injury is not understood. Here we will ask: 1) why do neurons improve when glial cells regenerate? Is this driven by a neuronal ligand or receptor for glial kon? 2) Is NFkB activated in glia by Toll receptors?

目的是以果蝇为模式生物，研究中枢神经系统(CNS)再生的分子机制。中枢神经系统在损伤后不会再生，从而导致永久性残疾，但大脑或脊髓的损伤和疾病会在神经胶质细胞中诱导有限的再生反应，如果了解这一点，可以利用这种反应来促进再生和修复。包被细胞系的神经胶质细胞(包裹轴突)分裂，产生营养因子，维持神经元的存活，帮助轴突重新生长和导航，并重新包裹轴突，导致有限的行为恢复。从昆虫到人类，这种反应在进化上是保守的，揭示了潜在的遗传机制。了解这一机制对于控制干细胞和祖细胞的增殖和分化以在体内进行治疗性激活和细胞移植至关重要。在BBSRC的资助下，伊达尔戈博士的团队发现了神经胶质再生反应背后的基因网络。它涉及Notch和Propero(PRO)基因，以及PRO和NFkB基因，这些基因共同启动细胞对损伤做出反应，实现快速反应并上调kon-tiki(Kon)的表达。和负反馈，关闭kon，恢复内稳态，终止对伤害的反应。Kon激活神经胶质细胞的增殖和分化，从而使神经胶质再生；Pros抑制细胞增殖，恢复内环境平衡，激活和维持神经胶质细胞分化。在与哺乳动物专家的合作中，伊达尔戈团队表明，这种基因网络在小鼠身上进化上是保守的。尽管如此，神经胶质细胞如何与神经元相互作用对损伤做出反应尚不清楚。在这里，我们将问：1)为什么当神经胶质细胞再生时，神经元会得到改善？这是由神经胶质细胞kon的神经元配体或受体驱动的吗？2)神经胶质细胞中的NFkB是否由Toll受体激活？

项目成果

Regenerative neurogenic response from glia requires insulin-driven neuron-glia communication.

• DOI: 10.7554/elife.58756
• 发表时间: 2021-02-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Harrison NJ;Connolly E;Gascón Gubieda A;Yang Z;Altenhein B;Losada Perez M;Moreira M;Sun J;Hidalgo A
• 通讯作者: Hidalgo A

Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

神经胶质细胞的再生神经反应需要胰岛素驱动的神经元-神经胶质细胞通讯

• DOI: 10.1101/721498
• 发表时间: 2019
• 作者: Harrison N