Sponsor
This work was supported by the National Institute of Mental Health (R01 MH113948-01A1), National Institute of Neurological Disorders and Stroke (R25NS089463), and Civitan International Research Center's Emerging Scholar award.
Published In
Genes Brain and Behavior
Document Type
Article
Publication Date
10-1-2025
Subjects
Autism -- neurodevelopmental disorders
Abstract
Large-scale human genetic studies implicate multiple genes that regulate protein ubiquitination in autism spectrum disorder (ASD). De novo loss-of-function mutations in the gene CULLIN3 (CUL3) are implicated in autism and intellectual disability (ID). CUL3 is an essential component of an E3 ubiquitin ligase complex required for ubiquitination of substrates, often a signal for proteasomal degradation. Homozygous deletion of Cul3 is embryonically lethal. Recent studies show heterozygous deletion of Cul3 results in phenotypes with some face validity for autism in constitutive and conditional Cul3 heterozygotes. To understand the function of Cul3 in late postnatal development and function in the brain, we crossed mice expressing Cre-recombinase under the control of the CaMKIIα promoter with conditional (floxed) Cul3 mice that resulted in viable homozygotes. In this study, we demonstrate that delayed postnatal deletion of Cul3 in predominantly forebrain excitatory neurons leads to robust behavioral differences across multiple behaviors. Cul3 conditional homozygotes show repetitive jumping, reduced marble burying, increased locomotion, impaired motor coordination, and increased hindlimb clasping. We were successfully able to replicate most of these findings in an independent cohort. Our future studies are aimed at gaining mechanistic insights into Cul3 function in the adult brain.
Rights
Copyright (c) 2025 The Authors
This work is licensed under a Creative Commons Attribution 4.0 International License.
Locate the Document
DOI
10.1111/gbb.70039
Persistent Identifier
https://archives.pdx.edu/ds/psu/44238
Citation Details
Sekar, P., Xia, Q., Stokes, A. C., Quan, F., Singer, J. D., & Powell, C. M. (2025). Cul3 Postnatal Homozygous Deletion in Forebrain Results in Behavioral Differences. Genes, Brain and Behavior, 24(5). Portico.