김재균 (University of Iowa) | 한빛사논문 > 한빛사

한빛사논문

조회340

김재균Jaekyoon Kim

University of Iowa

CV File 239 kb

Mol. Psychiatr., Jan 26 2024, | https://doi.org/10.1038/s41380-024-02411-0 Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders

Jaekyoon Kim^1,2, Yann Vanrobaeys^1,2,3, Benjamin Kelvington^1,2, Zeru Peterson^1,2,4, Emily Baldwin⁵, Marie E. Gaine^2,6, Thomas Nickl-Jockschat^1,2,4 and Ted Abel^1,2,4

¹Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa, IA, USA.

²Iowa Neuroscience Institute, University of Iowa, Iowa, IA, USA.

³Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa, IA, USA.

⁴Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa, IA, USA.

⁵The Iowa Medical Scientist Training Program, University of Iowa, Iowa, IA, USA.

⁶Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa, IA, USA

Corresponding authors : Correspondence to Thomas Nickl-Jockschat or Ted Abel.

Abstract

Neurodevelopmental disorders (NDDs) are polygenic in nature and copy number variants (CNVs) are ideal candidates to study the nature of this polygenic risk. The disruption of striatal circuits is considered a central mechanism in NDDs. The 16p11.2 hemi-deletion (16p11.2 del/+) is one of the most common CNVs associated with NDD, and 16p11.2 del/+ mice show sex-specific striatum-related behavioral phenotypes. However, the critical genes among the 27 genes in the 16p11.2 region that underlie these phenotypes remain unknown. Previously, we applied a novel strategy to identify candidate genes associated with the sex-specific phenotypes of 16p11.2 del/+ mice and highlighted three genes within the deleted region: thousand and one amino acid protein kinase 2 (Taok2), seizure-related 6 homolog-like 2 (Sez6l2), and major vault protein (Mvp). Using CRISPR/Cas9, we generated mice carrying null mutations in Taok2, Sez6l2, and Mvp (3 gene hemi-deletion (3g del/+)). Hemi-deletion of these 3 genes recapitulates sex-specific behavioral alterations in striatum-dependent behavioral tasks observed in 16p11.2 del/+ mice, specifically male-specific hyperactivity and impaired motivation for reward seeking. Moreover, RNAseq analysis revealed that 3g del/+ mice exhibit gene expression changes in the striatum similar to 16p11.2 del/+ mice exclusively in males. Subsequent analysis identified translation dysregulation and/or extracellular signal-regulated kinase signaling as plausible molecular mechanisms underlying male-specific, striatum-dependent behavioral alterations. Interestingly, ribosomal profiling supported the notion of translation dysregulation in both 3g del/+ and 16p11.2 del/+ male mice. However, mice carrying a 4-gene deletion (with an additional deletion of Mapk3) exhibited fewer phenotypic similarities with 16p11.2 del/+ mice. Together, the mutation of 3 genes within the 16p11.2 region phenocopies striatal sex-specific phenotypes of 16p11.2 del/+ mice. These results support the importance of a polygenic approach to study NDDs and underscore that the effects of the large genetic deletions result from complex interactions between multiple candidate genes.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-31)
연구진국외 연구진
분야

댓글 작성 로그인

CV 열람하기

연락처 보기