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Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders

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.

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Fig. 1: Generation of 3g del/+ mice.
Fig. 2: 3g del/+ mice reproduced sex-specific changes in striatal behavior.
Fig. 3: Gene expression changes in the striatum of male 3g del/+ mice are consistent with 16p11.2 del/+ males.
Fig. 4: Sex-specific changes in white matter during development in 3g del/+ mice.
Fig. 5: Additional hemi-deletion of Mapk3 does not increase molecular and behavioral alterations observed in 3g del/+ mice.

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Data availability

The dataset supporting the conclusions of this article is available in the NCBI’s Gene Expression Omnibus repository, GEO Series accession GSE224750.

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Acknowledgements

This work was supported by The University of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center (HAWK-IDDRC) P50 HD103556 (TA and Lane Strathearn, PI), the Roy J. Carver Chair in Neuroscience (TA), Interdisciplinary Graduate Program in Genetics at University of Iowa (YV), NIH grant R01 MH 087463 (TA), Simons Foundation Autism Research Initiative (SFARI) grant 345034 (TA), NIH grants T32 GM067795 and F31 MH134542 (BK), Eagles Autism Challenge (TN-J) and the Andrew H. Woods Professorship (TN-J). Transgenic mice were generated at the University of Iowa Genome Editing Core Facility directed by William Paradee, PhD and supported in part by grants from the NIH and from the Roy J. and Lucille A. Carver College of Medicine. We wish to thank Norma Sinclair, Patricia Yarolem, Joanne Schwarting and Rongbin Guan for their technical expertise in generating transgenic mice. The Neural Circuits and Behavior Core in the Iowa Neuroscience Institute provided equipment, facilities, and consultations services to support investigators in performing behavioral tasks. The Iowa Institute of Human Genetics provided Sanger DNA sequencing and RNA sequencing services. The Iowa Magnetic Resonance Research Facility provides access to a small animal MRI scanner as well as the necessary data processing equipment for animal MR imaging. We thank TB-SEQ, Inc. (Palo Alto, CA) for Ribosome profiling and helpful discussion.

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TA and TN-J conceptualized the project, supervised data collection and analysis. JK, TN-J, and TA wrote the manuscript with inputs from all the authors. JK, BK, and EB performed behavior, biochemical and molecular biology experiments. YV performed the bioinformatic analysis. ZP performed MRI imaging experiments and analysis. MEG conceptualized and designed the novel genetic mouse model.

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Correspondence to Thomas Nickl-Jockschat or Ted Abel.

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TA serves on the Scientific Advisory Board of EmbarkNeuro and is a scientific advisor to Aditum Bio and Radius Health.

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Kim, J., Vanrobaeys, Y., Kelvington, B. et al. Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders. Mol Psychiatry 29, 1310–1321 (2024). https://doi.org/10.1038/s41380-024-02411-0

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