SMPD4mediated sphingolipid metabolism regulates brain and primary cilia development

Abstract

SummaryGenetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study collected patients from twelve unrelated families with variants in the geneSMPD4, a neutral sphingomyelinase which metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These patients have severe developmental brain malformations including microcephaly and cerebellar hypoplasia. However, the mechanism ofSMPD4was not known and we pursued a new mouse model. We hypothesized that the role ofSMPD4in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells exhibit neural progenitor cell death and have shortened primary cilia which is rescued by adding exogenous ceramide.SMPD4production of ceramide is crucial for human brain development.