SMPD4-mediated sphingolipid metabolism regulates brain and primary cilia development.

IF 3.7 2区生物学 Q1 DEVELOPMENTAL BIOLOGY

Development Pub Date : 2024-11-15 DOI:10.1242/dev.202645

Katherine A Inskeep, Bryan Crase, Thamara Dayarathna, Rolf W Stottmann

引用次数: 0

Abstract

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.

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SMPD4介导的鞘脂代谢调节大脑和初级纤毛的发育。

多种鞘脂生物合成基因的遗传变异会导致人类脑部疾病。SMPD4 是一种中性鞘磷脂酶，在生物合成途径的早期将鞘磷脂代谢成神经酰胺。这些患者有严重的脑发育畸形，包括小头畸形和小脑发育不全。SMPD4 的发病机制尚不清楚，因此我们研究了一种新的小鼠模型。我们假设，SMPD4 在产生神经酰胺方面的作用对于初级纤毛的形成非常重要，而初级纤毛是介导细胞信号传导的重要细胞器。我们发现，该小鼠模型由于浦肯野细胞发育不良而导致小脑发育不良。人类诱导多能干细胞表现出神经祖细胞死亡，初级纤毛变短，而添加外源神经酰胺后，初级纤毛可以恢复。SMPD4产生的神经酰胺对人类大脑发育至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Development 生物-发育生物学

CiteScore

6.70

自引率

4.30%

发文量

433

审稿时长

3 months

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