Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Mol Sci. 2024 Aug 30;25(17):9469. doi: 10.3390/ijms25179469.
Human mutations of and are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated and mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of ; and ; larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of and resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in and mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of and in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.
和的人类突变已知与神经发育障碍（NDDs）有关，包括自闭症谱系障碍（ASDs）和精神分裂症（SZ）。然而，其潜在机制仍难以捉摸。在这项研究中，我们使用 CRISPR/Cas9 基因编辑技术生成了和突变的斑马鱼模型，这些模型表现出发育迟缓、大脑缺陷以及 NDD 的核心行为特征。对 ; 、; 和 ; 幼虫大脑的 RNA 测序分析揭示了影响突触传递、自噬、细胞凋亡、微管动力学、激素信号和昼夜节律调节的改变的基因表达谱。使用全胚胎原位杂交（WISH）和实时定量 PCR（qRT-PCR）进行验证证实了这些发现，支持了 RNA-seq 结果。此外，和的缺失导致全神经元 HuC 和神经元纤维网络 α-微管蛋白信号的显著下调。重要的是，长期低剂量暴露于环境内分泌干扰物（EEDs）加剧了和突变体的行为异常。这种综合方法增强了我们对 NDD 中遗传突变和环境因素之间复杂相互作用的理解。我们的发现为和在神经发育和行为调节中的作用提供了新的见解和实验基础，为未来针对 NDD 及相关病症的临床前药物筛选提供了框架。
