Membrane lipid metabolism as a regulatory frontier in neural crest biology: Roles for sphingolipids, cholesterol, and...

Neural crest cells are multipotent, migratory stem-like cells essential for vertebrate development that contribute broadly to many tissues including the craniofacial skeleton, peripheral nervous system, and pigment-producing cells. Their development progresses through phases of induction, specification, delamination, migration, and differentiation. Importantly, advancement through these phases requires detecting and responding to extracellular cues through the plasma membrane. While the gene regulatory networks and the signals that govern neural crest development are well characterized, plasma membrane lipid composition as a regulatory layer controlling these transitions remains underexplored. Despite technical limitations in quantitative lipid measurements from vertebrate embryos, genetic and molecular studies have inferred roles of key lipid metabolites. Here we review how membrane lipid metabolism and composition regulate neural crest behavior, focusing primarily on sphingolipids, cholesterol, and lipid raft domains. We examine how morphogen signaling is modified and organized by lipids, how modulating lipid content alters the biophysical state of the neural crest plasma membrane, and the deleterious effects of dysregulated lipid metabolism in neurocristopathies. Drawing parallels to other developmental and disease contexts, we highlight membrane lipid metabolism as a critical frontier in neural crest biology with broad implications for understanding developmental mechanisms and congenital disorders.