State Key Laboratory of Cardiovascular Diseases, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
Shanghai Arrhythmia Research Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
Cell Death Dis. 2024 Sep 30;15(9):710. doi: 10.1038/s41419-024-07088-5.
The spalt (Sal) gene family has four members (Sall1-4) in vertebrates, all of which play pivotal roles in various biological processes and diseases. However, the expression and function of SALL2 in development are still less clear. Here, we first charted SALL2 protein expression pattern during mouse embryo development by immunofluorescence, which revealed its dominant expression in the developing nervous system. With the establishment of Sall2 deficient mouse embryonic stem cells (ESCs), the in vitro neural differentiation system was leveraged to interrogate the function of SALL2, which showed impaired neural differentiation of Sall2 knockout (KO) ESCs. Furthermore, neural stem cells (NSCs) could not be derived from Sall2 KO ESCs and the generation of neural tube organoids (NTOs) was greatly inhibited in the absence of SALL2. Meanwhile, transgenic expression of E1 isoform of SALL2 restored the defects of neural differentiation in Sall2 KO ESCs. By chromatin immunoprecipitation sequencing (ChIP-seq), Tuba1a was identified as downstream target of SALL2, whose function in neural differentiation was confirmed by rescuing neural phenotypes of Sall2 KO ESCs when overexpressed. In sum, by elucidating SALL2 expression dynamics during early mouse development and mechanistically characterizing its indispensable role in neural differentiation, this study offers insights into SALL2's function in human nervous system development, associated pathologies stemming from its mutations and relevant therapeutic strategy.
Spalt (Sal) 基因家族在脊椎动物中有四个成员（Sall1-4），它们在各种生物学过程和疾病中都起着关键作用。然而，SALL2 在发育中的表达和功能仍不太清楚。在这里，我们首先通过免疫荧光法描绘了 SALL2 蛋白在小鼠胚胎发育过程中的表达模式，结果显示其在发育中的神经系统中表达占优势。通过建立 Sall2 缺失的小鼠胚胎干细胞（ESCs），我们利用体外神经分化系统来研究 SALL2 的功能，结果显示 Sall2 敲除（KO）的 ESCs 的神经分化受损。此外，Sall2 KO ESCs 不能分化为神经干细胞（NSCs），并且在没有 SALL2 的情况下，神经管类器官（NTOs）的生成也受到严重抑制。同时，E1 型 SALL2 的转基因表达恢复了 Sall2 KO ESCs 神经分化的缺陷。通过染色质免疫沉淀测序（ChIP-seq），鉴定出 Tuba1a 是 SALL2 的下游靶标，其在神经分化中的功能通过过表达 Sall2 KO ESCs 时挽救神经表型得到证实。总之，通过阐明 SALL2 在早期小鼠发育过程中的表达动态，并从机制上描述其在神经分化中的不可或缺的作用，本研究为 SALL2 在人类神经系统发育、源自其突变的相关病理以及相关治疗策略中的功能提供了新的见解。
