Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing

Jingzhen Li, Fei Liu, Yuexia Lv, Kui Sun, Yuntong Zhao, James Reilly, Yangjun Zhang, Jiayi Tu, Shanshan Yu, Xiliang Liu, Yayun Qin, Yuwen Huang, Pan Gao, Danna Jia, Xiang Chen, Yunqiao Han, Xinhua Shu, Daji Luo, Zhaohui Tang*, Mugen Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Dysfunction of splicing factors often result in abnormal cell differentiation and apoptosis, especially in neural tissues. Mutations in pre-mRNAs processing factor 31 (PRPF31) cause autosomal dominant retinitis pigmentosa, a progressive retinal degeneration disease. The transcriptome-wide splicing events specifically regulated by PRPF31 and their biological roles in the development and maintenance of retina are still unclear. Here, we showed that the differentiation and viability of retinal progenitor cells (RPCs) are severely perturbed in prpf31 knockout zebrafish when compared with other tissues at an early embryonic stage. At the cellular level, significant mitotic arrest and DNA damage were observed. These defects could be rescued by the wild-type human PRPF31 rather than the disease-associated mutants. Further bioinformatic analysis and experimental verification uncovered that Prpf31 deletion predominantly causes the skipping of exons with a weak 5′ splicing site. Moreover, genes necessary for DNA repair and mitotic progression are most enriched among the differentially spliced events, which may explain the cellular and tissular defects in prpf31 mutant retinas. This is the first time that Prpf31 is demonstrated to be essential for the survival and differentiation of RPCs during retinal neurogenesis by specifically modulating the alternative splicing of genes involved in DNA repair and mitosis.
Original languageEnglish
Number of pages17
JournalNucleic Acids Research
Early online date21 Jan 2021
DOIs
Publication statusE-pub ahead of print - 21 Jan 2021

Keywords

  • Prpf31
  • retinal progenitor cells
  • splicing

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