Very-long-chain fatty acids are crucial to neuronal polarity through lipid rafts

Fatty acids have long been considered essential for brain development, however, the involvement of fatty acid synthesis in nervous system formation is unclear. Our previous approaches using the proteomics of the growth cone revealed enrichment of the proteins involved in fatty acids (ref. 1), such as fatty acid synthase or fatty acid-binding proteins. To analyze how fatty acids contribute to the neuronal network formation, we generated mice with knockout of GPSN2, an enzyme involved in fatty acid elongation and synthesis of very long-chain fatty acids (VLCFA), and investigated the impact on nervous system formation. Both GPSN2 KO (embryonic lethal on day 9.5) and hetero (Ht) mice showed abnormal neuronal networks as a result of impaired neuronal polarity determination. Nontargeted lipidomics of GPSN2 KO embryos revealed that ceramide synthesis was specifically inhibited depending upon fatty acid length; namely, VLCFA-containing ceramide was reduced. Using several molecular markers, we demonstrated that lipid rafts were highly enriched in the wild type growth cone and GPSN2 Ht neurons lost gangliosides in the growth cone. Application of C24:0-ceramide, but not C16:0-ceramide or C24:0-phosphatidylcholine, to GPSN2 Ht neurons rescued both neuronal polarity determination and lipid raft density in the growth cone. Taken together, our results indicate that VLCFA synthesis, as a component of ceramide, contributes to physiological neuronal development in the brain network formation, in particular, neuronal polarity determination through the formation of lipid rafts (ref. 2).References: 1) Nozumi et al.: PNAS 106: 17211 (’09); 2) Honda et al.: Cell Rep 42: 113195 (’23)