FASN-dependent de novo lipogenesis is required for brain development

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

doi:10.1073/pnas.2112040119

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 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.

Highlights

Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development
There are two major classes of neural progenitor cells (NPCs): apical progenitors (APs) that divide in the ventricular zone (VZ) lining the ventricles and basal progenitor cells (BPs) that are derived from APs and divide within the subventricular zone (SVZ) to generate neuronal progeny [8,9,10,11,12]
Suggesting a role for fatty acid synthase (FASN) during embryonic brain development, we found an enrichment of FASN in the VZ compared to upper regions in the embryonic pallium at embryonic day (E) 14.5 (Fig. 1A and SI Appendix, Fig. S1A)

Summary

Introduction

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. 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. A role for de novo lipogenesis, a major metabolic process in which the multiprotein enzyme fatty acid synthase (FASN) converts glucose into palmitate, the building block for more complex fatty acids, in the context of embryonic brain development remains unexplored [19, 20]. To probe for a potential role of FASN-dependent lipogenesis in mammalian brain development, we conditionally deleted Fasn in the developing mouse cortex and in human embryonic stem cell (hESC)-derived forebrain organoids.

Methods

Results

Conclusion