{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T03:06:37Z","timestamp":1776481597682,"version":"3.51.2"},"reference-count":99,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["52002239"],"award-info":[{"award-number":["52002239"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Autism spectrum disorder (ASD) involves complex interactions between genetic and environmental factors. Recent studies suggest that dysregulation of \u03b2-arrestin2 (Arrb2) in the central nervous system is linked to ASD. However, its specific mechanisms remain unknown. Methods: This study employs a systems genetics approach to comprehensively investigate Arrb2 in multiple brain tissues, including the amygdala, cerebellum, hippocampus, and prefrontal cortex, using BXD recombinant inbred (RI) strains. In addition, genetic variance analysis, correlation analysis, expression quantitative trait loci (eQTL) mapping, and functional annotation were used to identify the key downstream targets of Arrb2, validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB). Results: Arrb2 exhibited expression variations across the four brain regions in BXD mice. eQTL mapping revealed that Arrb2 is cis-regulated, and increased Arrb2 expression levels were significantly correlated with ASD-like symptoms, such as impaired social interactions and abnormal learning and memory. Furthermore, protein\u2013protein interaction (PPI) network analysis, tissue correlation, functional relevance to autism, and differential expression identified eight downstream candidate genes regulated by Arrb2. The experimental results demonstrated that deletion of Arrb2 led to the downregulation of Myh9, Dnmt1, and Brd4 expression, along with protein kinase A (PKA)-induced hyperactivation of Synapsin I. These findings suggest that Arrb2 may contribute to the pathogenesis of autism by modulating the expression of these genes. Conclusions: This study highlights the role of Arrb2 in ASD pathogenesis and identifies Myh9, Dnmt1, and Brd4 as key downstream regulators. These findings provide new insights into the molecular mechanisms of ASD and pave the way for novel therapeutic targets.<\/jats:p>","DOI":"10.3390\/genes16050605","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T09:33:47Z","timestamp":1747733627000},"page":"605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Systems Genetics Reveals the Gene Regulatory Mechanisms of Arrb2 in the Development of Autism Spectrum Disorders"],"prefix":"10.3390","volume":"16","author":[{"given":"Junyu","family":"Xia","sequence":"first","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9023-1790","authenticated-orcid":false,"given":"Akhilesh K.","family":"Bajpai","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yamei","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lele","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yating","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Animal Science, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuxue","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9225-067X","authenticated-orcid":false,"given":"Shini","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1016\/j.cell.2022.03.042","article-title":"GPCR-Mediated \u03b2-Arrestin Activation Deconvoluted with Single-Molecule Precision","volume":"185","author":"Asher","year":"2022","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/s41401-020-00507-1","article-title":"Deficiency of \u03b2-Arrestin2 Exacerbates Inflammatory Arthritis by Facilitating Plasma Cell Formation","volume":"42","author":"Zhou","year":"2021","journal-title":"Acta Pharmacol. 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