Affiliation:
1. Zhejiang University School of Medicine Children's Hospital, National Clinical Research Center For Child Health
Abstract
Abstract
Fyn-related kinase (FRK) belonging to the Src family of non-receptor protein tyrosine kinases functions during the cell cycle. Here, we reported an autism spectrum disorders (ASD) patient with intragenic mutation of FRK with two other ASD risk genes. Circumventing the barrier of murine model studies, we generated the CRISPR/Cas9-engineered frk−/− zebrafish. We found that frk-knockout led to increased brain sizes. Frk−/− fish exhibited an ASD-like behavior, including impaired social communication, altered anxiety level, and cognitive dysfunction in both larvae and adults, which could be rescued by the transgenic neuron-specific re-expression of frk. GO and KEGG analysis of RNA-sequencing data found that the frk-knockout-induced DEGs were mainly concentrated in processes and functions related to cell metabolisms. PPI network analysis of the detected DEGs suggested that the cyp24a1/tp53 pathway may play a key role in frk-knockout-induced ASD. Furthermore, we found that the numbers of BrdU+ cells were significantly increased in the frk−/− larval brains. Cyp24a1-inhibition or tp53-activation, reduced cell proliferation and partially ameliorated social impairments in frk−/− zebrafish. Overall, our work established an ASD model of frk-knockout with assessable behavior phenotype in zebrafish and provided key insights into cell proliferation and the influence of cyp24a1/tp53 pathway-regulated cell proliferation on frk-knockout-induced ASD-like behaviors.
Publisher
Research Square Platform LLC