How are astrocytes made? Transcriptional regulation of astrocyte specification across development and adulthood.

神经胶质细胞（神经系统的非兴奋性成分）对大脑正常功能和体内平衡的重要性越来越被认识到，但我们对调节其产生和存活的因素的理解仍然不完整。该项目将使用跨学科的方法来研究Zeb1在大脑中神经胶质细胞的生成和维持中的作用。我们最近发现，海马体的成体神经干细胞中Zeb1的缺失以神经胶质细胞为代价增加了它们的神经元输出（Gupta et al. Cell Rep 2021）。这表明Zeb1在决定神经前体产生的细胞类型，使神经胶质细胞的产生，或抑制替代神经元命运方面的作用超出了干细胞维持。有趣的是，成熟的星形胶质细胞也表达Zeb1，这可能表明Zeb1调节其他星形胶质细胞特异性functions.The项目的目标是确定Zeb1是否是必要的神经胶质细胞的生产过程中的发展，并调查其在成熟的星形胶质细胞中的作用。为了实现这一目标，Zeb1将在不同的胚胎时间点从神经祖细胞的子集中选择性地消除，在神经胶质细胞开始产生之前或前后。Zeb1缺失对神经胶质细胞产生的影响将在出生后通过评估神经胶质细胞的数量、位置和形态来分析。这些实验将通过野生型和Zeb缺陷型祖细胞和星形胶质细胞的比较RNA测序分析来补充，因为作为转录因子，Zeb1可以激活或抑制其他基因的表达，这取决于它与哪些辅因子相关。这项分析将揭示Zeb1在不同细胞类型中控制的基因网络。最后，为了研究Zeb1在成熟星形胶质细胞中的作用，Zeb1将使用小鼠遗传学从出生后的星形胶质细胞中选择性地消除。将分析不同脑区星形胶质细胞的数量、位置和形态，并将结果与在胶质细胞发生前去除Zeb1的效果进行比较。该项目是三个实验室之间的跨学科合作，在发育神经科学、干细胞生物学和计算生物信息学方面具有丰富的经验。三人将共同监督该项目。他们的实验室位置很近，可以使用最先进的设备（例如，共聚焦和光片显微术）。

The importance of glial cells (the non-excitable component of the nervous system) for proper brain function and homeostasis is being increasingly recognized, but our understanding of the factors that regulate their production and survival is still incomplete. This project will use interdisciplinary approaches to investigate the role of Zeb1 in the generation and maintenance of glial cells in the brain.We have recently shown that loss of Zeb1 in adult neural stem cells of the hippocampus increases their neuronal output at the expense of glial cells (Gupta et al. Cell Rep 2021). This suggests a role for Zeb1 beyond stem cell maintenance in determining the type of cells produced by neural precursors, enabling the generation of glial cells, or suppressing an alternative neuronal fate. Interestingly, mature astrocytes also express Zeb1, which could indicate that Zeb1 regulates other astrocyte-specific functions.The goal of this project is to determine if Zeb1 is necessary for glial cell production during development and to investigate its roles in mature astrocytes. To accomplish this goal, Zeb1 will be selectively eliminated from a subset of neural progenitors at different embryonic timepoints, before or around the time when glial cells start to be produced. The impact of Zeb1 loss on glial cell production will be analyzed postnatally by assessing number, position and morphology of glial cells. Those experiments will be complemented by comparative RNA-Sequencing analysis of wild type and Zeb-deficient progenitors and astrocytes, because as a transcription factor, Zeb1 can activate or inhibit the expression of other genes, depending on which cofactors it associates with. This analysis will shed light on the networks of genes controlled by Zeb1 across different cell types. Finally, to investigate the role of Zeb1 in mature astrocytes, Zeb1 will be selectively eliminated from astrocytes postnatally using mouse genetics. Number, position and morphology of astrocytes in different brain regions will be analyzed and results compared to the effect of removing Zeb1 before the onset of gliogenesis.This project is an interdisciplinary collaboration between three laboratories with experiences in developmental neuroscience, stem cell biology and computational bioinformatics. All three will jointly supervise the project. Their laboratories are closely located and with access to state-of-the-art equipment (e.g., confocal and light sheet microscopy).