Regulation of Astrocyte Heterogeneity and Developmental Maturation in the CNS

描述(申请人提供)：星形胶质细胞现在被认为是成熟突触的活性成分；它们在结构上包裹突触并调节中枢神经系统(CNS)的神经传递。星形胶质细胞功能障碍与多种神经系统疾病有关，并被证明可以积极地调节疾病的进展。虽然星形胶质细胞经历了发育成熟的过程，亚型形成独特而精细的形态，并表达重叠但不同的分子特征，但尚不清楚星形胶质细胞异质性是如何在中枢神经系统发育过程中产生的，以及星形胶质细胞发育是如何调控的，部分原因是缺乏适当的研究工具。我们建议在果蝇和小鼠中使用整合的分子和遗传学方法来定义区分星形胶质细胞亚型的因素，并调节它们的发育成熟。该项目将特别关注这些目标：1)使用FACS和TRAP方法从分子上确定皮质内和不同中枢神经系统区域的星形胶质细胞亚型；2)进行基于dEAAT1的遗传筛选，以确定星形胶质细胞发育的调控因素；3)建立新的cre重组酶小鼠，用于研究星形胶质细胞在体内的异质性和功能。我们已经产生了大量的初步数据，证明了上述三个目标的可行性。通过表征中枢神经系统星形胶质细胞亚型的分子特征和确定星形胶质细胞发育的调控因子，该项目将为大脑皮层星形胶质细胞亚型提供标记，并对星形胶质细胞如何成熟提供新的见解。新的cre重组酶驱动鼠系的发展将促进皮层星形胶质细胞基因的选择性缺失/激活，而现有的星形胶质细胞cre驱动系对这一区域并不是很有效。了解星形胶质细胞的异质性和研究它的新工具对于了解星形胶质细胞如何变得功能失调以及不同类型的星形胶质细胞如何参与精神障碍的发病机制至关重要。

DESCRIPTION (provided by applicant): Astrocytes are now recognized as active components of mature synapses; they structurally ensheath synapses and modulate neurotransmission in the central nervous system (CNS). Astrocyte dysfunction has been implicated in various neurological disorders and has been shown to actively modulate disease progression. Although astrocytes undergo a developmental maturation process in which subtypes form unique and elaborate morphologies and express overlapping but distinct molecular signatures, it is unknown how astrocyte heterogeneity arises during development of the CNS and how astrocyte development is regulated, in part because of a lack of appropriate tools for such studies. We propose to use integrated molecular and genetic approaches in Drosophila and mouse to define factors that distinguish astrocyte subtypes and regulate their developmental maturation. In particular, this project will focus on these aims: 1) Molecularly define astrocyte subtypes within the cortex and in different CNS regions using FACS and TRAP approaches; 2) Perform dEAAT1-based genetic screens to identify regulators of astrocyte development; 3) Develop new cre recombinase mice for studying astrocyte heterogeneity and function in vivo. We have generated a large amount of preliminary data demonstrating feasibility for the three aims summarized above. By characterizing molecular signatures of astrocyte subtypes in the CNS and identifying regulators of astrocyte development, this project will provide markers for astrocyte subtypes in the cortex and novel insights about how astrocyte maturation occurs. The development of a new cre recombinase driver mouse line will facilitate the selective deletion/activation of genes in astrocytes of the cortex, a region for which an existing astrocyte cre driver line is not very effective. Knowledge of astrocyte heterogeneity and new tools for studying it are critical for understanding how astrocytes become dysfunctional and how distinct classes of astrocytes contribute to the pathogenesis of psychiatric disorders.