TY - JOUR
T1 - FASN-dependent de novo lipogenesis is required for brain development
AU - Gonzalez-Bohorquez, Daniel
AU - Gallego Lopez, Isabel M.
AU - Jaeger, Baptiste N.
AU - Pfammatter, Sibylle
AU - Bowers, Megan
AU - Semenkovich, Clay F.
AU - Jessberger, Sebastian
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported by the European Research Council (STEMBAR to S.J.), the Swiss National Science Foundation (BSCGI0_157859 and 310030_196869 to S.J.), the Zurich Neuroscience Center, the URPP (University research priority program) Adaptive Brain Circuits in Development and Learning of the University of Zurich (UZH), the Betty and David Koetser Foundation, and a Forschungskredit fellowship of UZH (to D.G.-B.). We thank K. Buthey, F. Sanchís-Calleja, and M. Quiniou for comments on the manuscript. We also thank the Flow Cytometry and Functional Genomic Center Core Facilities of UZH.
Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.
PY - 2022/1/11
Y1 - 2022/1/11
N2 - 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.
AB - 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.
KW - Lipogenesis
KW - Neural stem cell
KW - Neurogenesis
KW - Polarity
UR - http://www.scopus.com/inward/record.url?scp=85122673524&partnerID=8YFLogxK
U2 - 10.1073/pnas.2112040119
DO - 10.1073/pnas.2112040119
M3 - Article
C2 - 34996870
AN - SCOPUS:85122673524
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
M1 - e2112040119
ER -