Piezo1 regulates cholesterol biosynthesis to influence neural stem cell fate during brain development

• DOI: 10.1085/jgp.202213084
• Publication Date: 2022-09-07T14:03:20Z
• Authors: Jamison L. Nourse; Vivian M. Leung; Hamid Abuwarda; Elizabeth L. Evans; Esmeralda Izquier...; Alan T. Ly; Nguyen Truong; Samantha Smith; Harsh Bhavsar; Gabriella Bertaccini; Edwin S. Monuki; Mitradas M. Panicker; Medha M. Pathak
• Keywords: Piezo1; Neural Development

Mechanical forces and tissue mechanics influence the morphology of developing brain, but underlying molecular mechanisms have been elusive. Here, we examine role mechanotransduction in brain development by focusing on Piezo1, a mechanically activated ion channel. We find that Piezo1 deletion results thinner neuroepithelial layer, disrupts pseudostratification, reduces neurogenesis E10.5 mouse embryos. Proliferation differentiation knockout (KO) neural stem cells (NSCs) isolated from embryos are reduced vitro compared to littermate WT NSCs. Transcriptome analysis KO brains reveals downregulation cholesterol biosynthesis superpathway, which 16 genes, including Hmgcr, gene encoding rate-limiting enzyme pathway, downregulated 1.5-fold or more. Consistent with this finding, membrane lipid composition is altered, levels Cholesterol supplementation NSCs partially rescues phenotype vitro. These findings demonstrate for neurodevelopmental process modulates quantity, quality, organization influencing cellular metabolism. Our study establishes direct link between PIEZO1, intracellular levels, development.