Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Development. 2024 Nov 15;151(22). doi: 10.1242/dev.202645.
Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study looked at people from 12 unrelated families with variants in the gene SMPD4, a neutral sphingomyelinase that metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These individuals have severe developmental brain malformations, including microcephaly and cerebellar hypoplasia. The disease mechanism of SMPD4 was not known and so we pursued a new mouse model. We hypothesized that the role of SMPD4 in 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 lacking SMPD4 exhibit neural progenitor cell death and have shortened primary cilia, which is rescued by adding exogenous ceramide. SMPD4 production of ceramide is crucial for human brain development.
多种神经鞘脂生物合成基因中的遗传变异会导致人类大脑疾病。最近的一项研究观察了 12 个无血缘关系的家族中 SMPD4 基因突变的患者，SMPD4 基因是一种中性鞘磷脂酶，可在鞘脂生物合成途径的早期将鞘磷脂代谢为神经酰胺。这些个体存在严重的发育性脑畸形，包括小头畸形和小脑发育不良。SMPD4 的疾病机制尚不清楚，因此我们构建了一个新的小鼠模型。我们假设 SMPD4 在产生神经酰胺方面的作用对于产生初级纤毛至关重要，初级纤毛是一种介导细胞信号的关键细胞器。我们发现，由于浦肯野细胞发育失败，该小鼠模型存在小脑发育不良。缺乏 SMPD4 的人类诱导多能干细胞表现出神经祖细胞死亡，并具有缩短的初级纤毛，添加外源性神经酰胺可挽救这一现象。神经酰胺的 SMPD4 生成对于人类大脑发育至关重要。
