CRISPR敲除筛选揭示了神经元分化和PEDS1在神经发育中所必需的基因和途径，这一成果由耶路撒冷的希伯来大学Sagiv Shifman研究团队经过不懈努力而取得。相关论文于2026年1月5日发表在《自然—神经科学》杂志上。

在这里，课题组人员证明了在分化为神经谱系的同主题胚胎干细胞中进行全基因组CRISPR敲除筛选鉴定了数百个必需基因，其中只有少数基因目前与NDD有关。显性NDD基因富集于转录调控因子，而隐性NDD基因主要参与代谢过程。8个基因（Eml1、Dthemp26、Dynlrb2、Mta3、Peds1、Sgms1、Slitrk4和Vamp3）的小鼠模型显示出明显的神经解剖学异常，包括一半的病例出现小头畸形。研究人员在小头畸形、整体发育迟缓和先天性白内障患者中发现了一种双等位基因变异，这是一种浆磷脂原生物合成的关键酶PEDS1。在小鼠中，Peds1缺失导致细胞周期退出加速，神经元分化和迁移受损。这些神经分化所需的通路为发现其他NDD基因提供了遗传框架。

据介绍，神经发育障碍（NDDs）是由大脑发育中断引起的，但其潜在的途径仍不完全清楚。

附：英文原文

Title: CRISPR knockout screens reveal genes and pathways essential for neuronal differentiation and implicate PEDS1 in neurodevelopment

Author: Amelan, Alana, Collins, Stephan C., Damseh, Nadirah S., Hamada, Nanako, Salim, Ahd, Dvir, Elad, Monderer-Rothkoff, Galya, Harel, Tamar, Nagata, Koh-ichi, Yalcin, Binnaz, Shifman, Sagiv

Issue&Volume: 2026-01-05

Abstract: Neurodevelopmental disorders (NDDs) arise from disruptions in brain development, yet the underlying pathways remain incompletely understood. Here we demonstrate that genome-wide CRISPR knockout screens in mouse embryonic stem cells differentiating into neural lineages identify hundreds of essential genes, only a minority of which are currently implicated in NDDs. Dominant NDD genes were enriched for transcriptional regulators, whereas recessive NDD genes were predominantly involved in metabolic processes. Mouse models for eight genes (Eml1, Dusp26, Dynlrb2, Mta3, Peds1, Sgms1, Slitrk4 and Vamp3) revealed marked neuroanatomical abnormalities, including microcephaly in half of the cases. Focusing on PEDS1, a key enzyme in plasmalogen biosynthesis, we identified a bi-allelic variant in individuals with microcephaly, global developmental delay and congenital cataracts. In mice, Peds1 deficiency led to accelerated cell-cycle exit and impaired neuronal differentiation and migration. These pathways required for neural differentiation provide a genetic framework for discovering additional NDD genes.

DOI: 10.1038/s41593-025-02165-0

Source: https://www.nature.com/articles/s41593-025-02165-0