Molecular Mechanisms of Astrocyte Growth Control.

星形胶质细胞对大脑功能至关重要，塑造神经元及其连接并支持其活动。星形胶质细胞获得了非常复杂的形态学，以相互关联，并在突触中调节突触发生，神经递质再摄取，代谢支持，离子平衡，并最终调节动物行为。虽然人们认为这种形态对于星形胶质细胞的有效功能是绝对必要的，但星形胶质细胞如何获得这种异常复杂的结构仍然是一个谜。这是令人惊讶的，因为星形胶质细胞生长控制的破坏会导致最棘手和致命的人类脑肿瘤，胶质母细胞瘤。 星形胶质细胞是如何获得其显著的形态的，它们又是如何组织其亚细胞结构以实现其多种功能的？我将尝试用果蝇星形胶质细胞作为模型来回答这些核心问题。果蝇星形胶质细胞在形态、发育、分子和功能方面与哺乳动物星形胶质细胞非常相似。我将开始通过检查~30个标记细胞器的遗传编码标记的分布来全面表征星形胶质细胞的细胞器景观（目标1）。这将使我能够定义星形胶质细胞的基本细胞器结构，这是理解它们复杂的形态如何在超微结构上排列以及它如何决定功能的重要第一步。这些细胞标志也将使影响星形胶质细胞形态的突变体的严格分析成为可能。在目标2中，我将对星形胶质细胞生长控制途径进行第一次无偏正向遗传筛选。为此，我们基于MARCM技术在果蝇中建立了一个独特的遗传筛选平台，该平台允许筛选整个基因组的各种表型，包括生长增加，增殖变化或星形胶质细胞形态的其他变化。定义星形胶质细胞如何控制它们的细胞生长，浸润和平铺对于理解星形胶质细胞如何影响大脑健康和疾病至关重要。由于这将是星形胶质细胞生长控制途径的第一个正向遗传筛选，大量令人兴奋的突变体等待发现。新的保守的细胞通路将是我的重点，这样在苍蝇中的发现可以在脊椎动物中翻译。

Astrocytes are essential to brain function, shaping neurons and their connections and supporting their activity. Astrocytes acquire a remarkably complex morphology to associate with each other, and synapses where they regulate synaptogenesis, neurotransmitter reuptake, metabolic support, ion balance, and ultimately animal behavior. While it is believed that this morphology is absolutely essential for efficient astrocyte function, how astrocytes acquire this unusually complex architecture remains a mystery. This is surprising in light of the fact that disruption of astrocyte growth control results in the most intractable and deadly human brain tumor, glioblastoma. How do astrocytes acquire their remarkably morphology, and how do they organize their subcellular architecture to enable their diverse functions? I will attempt to answer these central questions using Drosophila astrocytes as a model. Fly astrocytes are remarkably similar to their mammalian counterparts by morphological, developmental, molecular, and functional criteria. I will begin by comprehensively characterizing the cell-wide organellar landscape of astrocytes by examining the distribution of ~30 genetically encodable markers that label cellular organelles (Aim 1). This will allow me to define the basic organellar architecture of astrocytes, which is an essential first step toward understanding how their intricate morphology is arranged ultrastructurally and how it dictates function. These cellular landmarks will also enable a rigorous analysis of mutants that affect astrocyte morphology. In Aim 2, I will perform the first unbiased forward genetic screen for astrocyte growth control pathways. We have established a unique genetic screening platform for this purpose in Drosophila based on MARCM technology, which allows for screening of the entire genome for a variety of phenotypes including increased growth, changes in proliferation, or other changes in astrocyte morphology. Defining how astrocytes control their cell growth, infiltration, and tiling is critical to understanding how astrocytes affect brain health and disease. Since this will be the first forward genetic screen for astrocyte growth control pathways, a wealth of exciting mutants await discovery. Novel conserved cellular pathways will be my focus, such that discoveries in the fly can be next translated in vertebrates.