Mutations in the microexon splicing regulator srrm4 have minor phenotypic effects on zebrafish neural development.

IF 2.2 3区 生物学 Q3 GENETICS & HEREDITY G3: Genes|Genomes|Genetics Pub Date : 2025-05-08 DOI:10.1093/g3journal/jkaf052
Tripti Gupta, Gennady Margolin, Harold A Burgess
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Abstract

Achieving a diversity of neuronal cell types and circuits during brain development requires alternative splicing of developmentally regulated mRNA transcripts. Microexons are a type of alternatively spliced exon that are 3-27 nucleotides in length and are predominantly expressed in neuronal tissues. A key regulator of microexon splicing is the RNA-binding protein Serine/arginine repetitive matrix 4 (Srrm4). Srrm4 is a highly conserved, vertebrate splicing factor that is part of an ancient family of splicing proteins. To better understand the function of Srrm4 during brain development, we examined the neural expression of zebrafish srrm4 from 1 to 5 days of development using fluorescence in situ hybridization. We found that srrm4 has a dynamically changing expression pattern, with expression in diverse cell types and stages during development. We then used CRISPR-based mutagenesis to generate zebrafish srrm4 mutants. Unlike previously described morphant phenotypes, srrm4 mutants did not show overt morphological defects. Whole-brain morphometric analysis revealed a reduction in optic tectum neuropil in G0 crispants that, unexpectedly, was also not replicated in stable mutants. Sequencing of wild-type and mutant transcriptomes revealed only minor changes in splicing and did not support a hypothesis of transcriptional adaptation, suggesting that another, as yet, unidentified mechanism of compensation is occurring. srrm4 thus appears to have a limited role in zebrafish neural development.

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微外显子剪接调节因子srrm4的突变对斑马鱼神经发育有轻微的表型影响。
在大脑发育过程中实现神经元细胞类型和回路的多样性需要对发育调节的mRNA转录物进行选择性剪接。微外显子是一种选择性剪接的外显子,长度为3-27个核苷酸,主要在神经组织中表达。微外显子剪接的关键调节因子是rna结合蛋白丝氨酸/精氨酸重复基质4 (Srrm4)。Srrm4是一种高度保守的脊椎动物剪接因子,是一个古老的剪接蛋白家族的一部分。为了更好地了解Srrm4在大脑发育过程中的功能,我们使用荧光原位杂交技术检测了斑马鱼发育1-5天Srrm4的神经表达。我们发现srrm4具有动态变化的表达模式,在不同的细胞类型和发育阶段都有表达。然后,我们使用基于crispr的诱变技术产生斑马鱼srrm4突变体。与先前描述的形态表型不同,srrm4突变体没有表现出明显的形态缺陷。全脑形态分析显示,G0 crispants的视顶神经pil减少,出乎意料的是,在稳定突变体中也没有复制。野生型和突变型转录组的测序显示,剪接只发生了微小的变化,并且不支持转录适应的假设,这表明另一种尚未确定的补偿机制正在发生。因此,Srrm4似乎在斑马鱼的神经发育中作用有限。
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来源期刊
G3: Genes|Genomes|Genetics
G3: Genes|Genomes|Genetics GENETICS & HEREDITY-
CiteScore
5.10
自引率
3.80%
发文量
305
审稿时长
3-8 weeks
期刊介绍: G3: Genes, Genomes, Genetics provides a forum for the publication of high‐quality foundational research, particularly research that generates useful genetic and genomic information such as genome maps, single gene studies, genome‐wide association and QTL studies, as well as genome reports, mutant screens, and advances in methods and technology. The Editorial Board of G3 believes that rapid dissemination of these data is the necessary foundation for analysis that leads to mechanistic insights. G3, published by the Genetics Society of America, meets the critical and growing need of the genetics community for rapid review and publication of important results in all areas of genetics. G3 offers the opportunity to publish the puzzling finding or to present unpublished results that may not have been submitted for review and publication due to a perceived lack of a potential high-impact finding. G3 has earned the DOAJ Seal, which is a mark of certification for open access journals, awarded by DOAJ to journals that achieve a high level of openness, adhere to Best Practice and high publishing standards.
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