Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration

Abstract

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography–tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.