Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation
Journal
Human Molecular Genetics
Journal Volume
21
Journal Issue
19
Pages
4270-4285
Date Issued
2012
Author(s)
Chen C.-Y.
Tsai M.-S.
Lin C.-Y.
Yu I.-S.
Lin S.-R.
Juan L.-W.
Hsu H.-M.
Abstract
Mutation in CUL4B, which encodes a scaffold protein of the E3 ubiquitin ligase complex, has been found in patients with X-linked mental retardation (XLMR). However, early deletion of Cul4b in mice causes prenatal lethality, which has frustrated attempts to characterize the phenotypes in vivo. In this report, we successfully rescued Cul4b mutant mice by crossing female mice in which exons 4-5 of Cul4b were flanked by loxP sequences with Sox2-Cre male mice. In Cul4b-deficient (Cul4bδ/Y) mice, no CUL4B protein was detected in any of the major organs, including the brain. In the hippocampus, the levels of CUL4A, CUL4B substrates (TOP1, β-catenin, cyclin E and WDR5) and neuronal markers (MAP2, tau-1, GAP-43, PSD95 and syn-1) were not sensitive to Cul4b deletion, whereas the number of parvalbumin (PV)-positive GABAergic interneurons was decreased in Cul4bδ/Y mice, especially in the dentate gyrus (DG). Some dendritic features, including the complexity, diameter and spine density in the CA1 and DG hippocampal neurons, were also affected by Cul4b deletion. Together, the decrease in the number of PV-positive neurons and altered dendritic properties in Cul4bδ/Y mice imply a reduction in inhibitory regulation and dendritic integration in the hippocampal neural circuit, which lead to increased epileptic susceptibility and spatial learning deficits. Our results identify Cul4bδ/Y mice as a potential model for the non-syndromic model of XLMR that replicates the CUL4B-associated MR and is valuable for the development of a therapeutic strategy for treating MR. ? The Author 2012. Published by Oxford University Press. All rights reserved.
SDGs
Other Subjects
albumin; beta catenin; cre recombinase; cullin; cullin 4A; cullin 4B; cyclin E; DNA topoisomerase; microtubule associated protein 2; neuromodulin; postsynaptic density protein 95; protein; synapsin I; tau protein; transcription factor Sox2; unclassified drug; WDR5 protein; animal cell; animal experiment; animal model; animal tissue; article; controlled study; dendrite; dentate gyrus; disease model; DNA sequence; epilepsy; exon; female; GABAergic system; gene deletion; genetic engineering; genetic susceptibility; hippocampal CA1 region; hippocampus; interneuron; learning disorder; LoxP site; male; mouse; mouse mutant; nerve cell network; nonhuman; priority journal; protein localization; spatial learning deficit; X linked mental retardation; Animals; Cullin Proteins; Disease Models, Animal; Female; Genetic Engineering; Humans; Male; Mental Retardation, X-Linked; Mice; Mice, Inbred C57BL; Mice, Knockout; Mus
Type
journal article