<br>SASH1 有助于中枢神经系统早期发育中的神经胶质细胞迁移,Developmental Biology

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SASH1 有助于中枢神经系统早期发育中的神经胶质细胞迁移
Developmental Biology ( IF 2.5 ) Pub Date : 2023-09-22 , DOI: 10.1016/j.ydbio.2023.09.006
Zhihao Zhou ₁ , Penghui Wang ₂ , Qing Wang ₁ , Zhangji Dong ₁ , Xu Chen ₁ , Run Zhuo ₁ , Ronghua Wu ₁ , Yan Liu ₁ , Liu Yang ₂ , Mei Liu ₁

Affiliation

SAM 和 SH3 结构域包含 1 （SASH1）是 SLy 蛋白家族的一员，是一种肿瘤抑制基因，因其与各种癌症的相关性而被研究。SASH1 在哺乳动物中枢神经系统中高度表达，尤其是在神经胶质细胞中，并且在斑马鱼胚胎发育过程中在中枢神经系统中表达。然而，SASH1 在大脑发育中的作用很少被研究。在这项研究中，使用吗啉寡核苷酸（MO）下调斑马鱼中 sash1a 的表达，以观察大脑的形态变化。选择三个转基因斑马鱼品系 Tg（gfap：eGFP）、Tg（hb9：eGFP）和 Tg（coro1a：eGFP），观察 sash1a 敲低后神经胶质细胞、神经元和免疫细胞的变化。我们的结果表明，居住在发育大脑中的小胶质细胞数量减少，而尾部初级运动神经元的轴突生长不受 sash1a 下调的影响。更重要的是，gfap+ 神经胶质细胞在 sash1a 形态中表现出异常排列和无序方向。在注射 cas9 mRNA 和 sash1a sgRNA 诱导的突变中验证了相似的表型。我们进一步对在单细胞期注射 sash1a MO 的斑马鱼幼虫进行了行为实验，发现它们表现出异常的行为轨迹。此外，注射人 SASH1 mRNA 在 sash1a MO 斑马鱼中挽救了这些现象。综上所述，我们的研究揭示了 SASH1 的下调导致胚胎脑畸形和神经胶质细胞编组紊乱，表明 SASH1 在胚胎脑发育过程中神经胶质细胞的迁移中起重要作用。

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SASH1 contributes to glial cell migration in the early development of the central nervous system

SAM and SH3 domain-containing 1 (SASH1), a member of the SLy protein family, is a tumor suppressor gene that has been studied for its association with various cancers. SASH1 is highly expressed in the mammalian central nervous system, particularly in glial cells, and is expressed in the central nervous system during zebrafish embryo development. However, SASH1's role in brain development has rarely been investigated. In this study, Morpholino oligonucleotides (MO) were used to down-regulate sash1a expression in zebrafish to observe morphological changes in the brain. Three transgenic zebrafish lines, Tg(gfap:eGFP), Tg(hb9:eGFP), and Tg(coro1a:eGFP) were selected to observe changes in glial cells, neurons, and immune cells after sash1a knockdown. Our results showed that the number of microglia residing in the developmental brain was reduced, whereas the axonal growth of caudal primary motor neurons was unaffected by sash1a downregulation. And more significantly, the gfap + glia presented abnormal arrangements and disordered orientations in sash1a morphants. The similar phenotype was verified in the mutation induced by the injection of cas9 mRNA and sash1a sgRNA. We further performed behavioral experiments in zebrafish larvae that had been injected with sash1a MO at one-cell stage, and found them exhibiting abnormal behavior trajectories. Moreover, injecting the human SASH1 mRNA rescued these phenomena in sash1a MO zebrafish. In summary, our study revealed that the downregulation of SASH1 leads to malformations in the embryonic brain and disorganization of glial cell marshalling, suggesting that SASH1 plays an important role in the migration of glial cells during embryonic brain development.

更新日期：2023-09-22

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