Regulation of astroglial branch morphogenesis during visual circuit assembly in Drosophila

果蝇视路组装过程中星形胶质细胞分支形态发生的调节

• 批准号: BB/S00386X/1
• 负责人: Iris Salecker
• 金额: $ 50.88万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS00386X%2F1
• 关键词: Regulation; astroglial; branch; morphogenesis; during

Within our brains, neurons generally exist in a close partnership with different glial subtypes. Astrocytes play a critical role in controlling neural circuit development, function and homeostasis. Although the number and size of astrocytes correlates with brain size and cognitive abilities, they adopt remarkably complex morphologies with veil-like processes that ensheath the cell bodies and axonal and dendritic arborizations of neurons in both vertebrate and invertebrate nervous systems. While all astrocytes have common core physiological properties, they constitute a heterogeneous population with distinct morphologies in different brain regions. Much progress has been made in uncovering the molecular mechanisms that control neuronal morphology and connectivity. However, the fundamental question how astrocytes acquire their distinct shapes has received little attention and only a limited number of determinants has so far been identified to play a role in this important biological process.The fruit fly Drosophila melanogaster is a powerful model organism for determining the function of known or novel genes in cells and tissues of interest. Considering the high degree of evolutionary conservation of genetic functions, insights gained in Drosophila are highly relevant for studies in mammals, including humans. In this study, we use the visual system of Drosophila to uncover the genes required for correct branch morphogenesis of astrocyte-like glia. Previously, we have identified an astrocyte-like glial subtype with stereotypic fine columnar and layered processes that is well suited for functional genetic studies during development. We have found a novel transmembrane Leucine-rich repeat domain containing cell surface molecule, called Lapsyn, that is essential for glial branch extension into the synaptic neuropil. Outlined research in this proposal seeks to gain insights how Lapsyn functions molecularly to deepen our knowledge of glial branch morphogenesis. Based on our earlier genetic studies we hypothesize that Lapsyn controls branch extension of astrocyte-like glia in response to neuronal membrane-bound or secreted determinants. Preliminary data suggest that in astrocyte-like glia, Lapsyn likely does not function as a receptor but as a co-receptor or structural cell surface proteins which interact with cytoskeletal regulators and components in a complex via other cell surface molecules. We therefore aim to identify the upstream and downstream binding partners of Lapsyn in an unbiased manner and to characterize their function in detail. Furthermore, to enhance our understanding of the significance of correct branch extension of astrocyte-like glia for neuronal connectivity and function, we will examine the link between branch extension and synapse formation and assess their participation in circuit activity. At long term, these insights into normal astrocyte development will advance our understanding of astrocyte-specific genetic contributions to neurodevelopmental and neurodegenerative disorders in humans.

在我们的大脑中，神经元通常与不同的神经胶质亚型密切合作。星形胶质细胞在控制神经回路发育、功能和稳态方面发挥着关键作用。虽然星形胶质细胞的数量和大小与大脑大小和认知能力相关，但它们采用非常复杂的形态，具有面纱样过程，这些过程包裹脊椎动物和无脊椎动物神经系统中神经元的细胞体和轴突和树突分支。虽然所有星形胶质细胞具有共同的核心生理特性，但它们构成了在不同脑区域具有不同形态的异质群体。在揭示控制神经元形态和连接的分子机制方面已经取得了很大进展。然而，星形胶质细胞如何获得其独特的形状的基本问题很少受到关注，只有有限数量的决定因素已被确定发挥作用，迄今为止，在这一重要的生物学过程中，果蝇是一个强大的模式生物，用于确定已知的或新的基因在细胞和组织中的功能感兴趣。考虑到遗传功能的高度进化保守性，在果蝇中获得的见解与哺乳动物（包括人类）的研究高度相关。在这项研究中，我们使用果蝇的视觉系统，以揭示正确的星形胶质细胞样胶质细胞分支形态发生所需的基因。以前，我们已经确定了一个星形胶质细胞样胶质细胞亚型与刻板的细柱状和分层的过程，非常适合在发展过程中的功能遗传学研究。我们发现了一种新的跨膜富含亮氨酸重复结构域的细胞表面分子，称为Lapsyn，这是必要的神经胶质分支延伸到突触神经元。该提案中概述的研究旨在深入了解Lapsyn分子如何发挥作用，以加深我们对神经胶质分支形态发生的了解。基于我们早期的遗传学研究，我们假设Lapsyn控制星形胶质细胞样胶质细胞的分支延伸，以响应神经元膜结合或分泌的决定簇。初步数据表明，在星形胶质细胞样神经胶质细胞中，Lapsyn可能不作为受体发挥作用，而是作为共受体或结构细胞表面蛋白，其通过其他细胞表面分子与细胞骨架调节剂和复合物中的组分相互作用。因此，我们的目标是以公正的方式确定Lapsyn的上游和下游结合伙伴，并详细描述其功能。此外，为了加强我们对星形胶质细胞样胶质细胞正确分支延伸对神经元连接和功能的重要性的理解，我们将研究分支延伸和突触形成之间的联系，并评估它们参与回路活动。从长远来看，这些对正常星形胶质细胞发育的见解将促进我们对星形胶质细胞特异性遗传对人类神经发育和神经退行性疾病的贡献的理解。