The Novel Role of Cilia in Astrocyte Sevelopment

项目总结 星形胶质细胞是大脑中含量最丰富的胶质细胞，对神经回路的形成和神经元是必不可少的。 功能。星形胶质细胞在发育中的大脑中起着不可或缺的作用，但我们对 星形胶质细胞是如何发育的，与我们对神经元发育的知识相去甚远。为了发育，星形胶质细胞必须在 适当的时间，遗传分化，形态成熟。星形胶质细胞功能障碍导致 几种神经发育障碍的病理，但这些机制还知之甚少。两者都有 神经元和星形胶质细胞具有初级纤毛，这是一种细长的微管突起，用作 小区专用信令中心。纤毛是神经元发育的重要调节因子。然而，尽管 星形胶质细胞具有初级纤毛，其纤毛功能尚不清楚。纤毛的中断导致 一种称为纤毛病变的疾病，通常会导致一系列神经异常。我们必须 建立对星形胶质细胞纤毛的基本了解，因为它们很可能对 神经发育疾病。我的研究目标是创建关于以下角色的基础知识 纤毛在星形胶质细胞发育中发挥作用。我的初步数据表明，星形胶质细胞纤毛是几种 星形胶质细胞发育的各个阶段。星形胶质细胞纤毛丢失导致增殖改变，细胞异常 形态和发育中的星形胶质细胞基因表达中断。因此，我假设 星形胶质细胞纤毛是调节星形胶质细胞增殖和分化的关键。该项目旨在1)确定 纤毛如何调控星形胶质细胞的增殖；2)确定纤毛在星形胶质细胞分化中的作用。我会用 在不同的时间点通过基因消融纤毛的小鼠模型，特别是在星形胶质细胞中，以研究 星形胶质细胞发育不同阶段对纤毛的需求。我会决定纤毛是否会调节 星形胶质细胞增殖的时间和速度。然后，为了进一步定义纤毛如何调节增殖，我将监测 细胞周期进程。下一步，我将通过进行一个 星形胶质细胞大小、间距和分支特征的形态分析。最后，我将进行一次 转录组分析，以确定纤毛是否调节发育中的星形胶质细胞的遗传程序。这就做 还要在细胞水平上检测星形胶质细胞的转录表达，以确定纤毛是否会影响 皮质星形胶质细胞特定群体的分化。拟议中的实验将揭示新的 并为纤毛信号在星形胶质细胞发育中的作用奠定了基础。 这项工作将增加关于星形胶质细胞纤毛以及星形胶质细胞如何发育完善的基础知识。 我们对星形胶质细胞在神经发育疾病中的作用的理解。

PROJECT SUMMARY Astrocytes are the most abundant glial cell in the brain and are essential for neural circuit formation and neuron function. Astrocytes have an indispensable role in the developing brain, yet our fundamental understanding of how astrocytes develop trails our knowledge of neuron development. To develop, astrocytes must proliferate at the proper time, genetically differentiate, and morphologically mature. Astrocyte dysfunction contributes to the pathology of several neurodevelopmental disorders, yet these mechanisms are poorly understood. Both neurons and astrocytes possess a primary cilium, a slender microtubule projection, that serves as a specialized signaling center for the cell. Cilia are critical regulators of neuron development. However, despite astrocytes having a primary cilium, the function of astrocyte cilia remains unknown. Disruptions to cilia result in a class of disorders termed ciliopathies that often result in a spectrum of neurological abnormalities. We must establish a fundamental understanding of astrocyte cilia because it is likely that they contribute to such neurodevelopmental diseases. The goal of my research is to create foundational knowledge of the roles that cilia play in astrocyte development. My preliminary data indicate that astrocyte cilia are necessary for several stages of astrocyte development. Loss of astrocyte cilia results in altered proliferation, abnormal cellular morphology, and disrupted expression of developmental astrocyte genes. Therefore, I hypothesize that astrocyte cilia are critical to regulate astrocyte proliferation and differentiation. This project aims to 1) determine how cilia regulate astrocyte proliferation and 2) define the role of cilia in astrocyte differentiation. I will use mouse models to genetically ablate cilia at distinct timepoints, specifically in astrocytes, to investigate the requirements of cilia at different stages of astrocyte development. I will determine whether cilia regulate the timing and rate of astrocyte proliferation. Then, to further define how cilia regulate proliferation, I will monitor cell cycle progression. Next, I will define whether cilia are required for astrocyte differentiation by conducting a morphological analysis of astrocyte size, spacing, and branching features. Finally, I will conduct a transcriptomics analysis to determine whether cilia regulate the genetic program of developing astrocytes. I will also examine astrocyte transcriptional expression at the cellular level to define whether cilia impact differentiation in specific populations of cortical astrocytes. The proposed experiments will reveal novel functions of astrocyte cilia and establish a foundation for the roles of ciliary signaling in astrocyte development. This work will increase fundamental knowledge about astrocyte cilia and how astrocytes develop to improve our understanding of astrocyte contribution to neurodevelopmental diseases.