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标题：FASN-dependent de novo lipogenesis is required for brain development
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作者：Daniel Gonzalez-Bohorquez ; Isabel M. Gallego López ; Baptiste N. Jaeger 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：2
DOI：10.1073/pnas.2112040119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Regulation of cellular metabolism in proliferating progenitor cells and their neuronal progeny is critical for brain development and function. Here, we identify a pivotal role of fatty acid synthase (FASN)-dependent de novo lipogenesis for mouse and human brain development, as genetic deletion of FASN leads to microcephaly in the developing mouse cortex and cortical malformations in human embryonic stem cell–derived forebrain organoids. Mechanistically, we show that FASN is required for proper polarity of apical progenitor cells. The dual approach applied here, using mouse genetics and human forebrain organoids, establishes a role of FASN-dependent lipogenesis for mouse and human brain development and identifies a link between progenitor-cell polarity and lipid metabolism. Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors and reduced progenitor proliferation. Furthermore, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell–derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity in human brain organoids. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor-cell polarity and lipid metabolism.
关键词：enneurogenesisneural stem celllipogenesispolarity