FASN-dependent de novo lipogenesis is required for brain development

Daniel Gonzalez-Bohorquez, Isabel M. Gallego Lopez, Baptiste N. Jaeger, Sibylle Pfammatter, Megan Bowers, Clay F. Semenkovich, Sebastian Jessberger

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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 Emx1Cremediated, 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.

Original languageEnglish
Article numbere2112040119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number2
DOIs
StatePublished - Jan 11 2022

Keywords

  • Lipogenesis
  • Neural stem cell
  • Neurogenesis
  • Polarity

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