title: Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation.
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 (Cul4b(Δ)/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 Cul4b(Δ)/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 Cul4b(Δ)/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 Cul4b(Δ)/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.
authors: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors: Chun-Yu
authors: CY
authors: Chen
authors: Ming-Shian
authors: MS
authors: Tsai
authors: Chien-Yu
authors: CY
authors: Lin
authors: I-Shing
authors: IS
authors: Yu
authors: You-Tzung
authors: YT
authors: Chen
authors: Shu-Rung
authors: SR
authors: Lin
authors: Liang-Wen
authors: LW
authors: Juan
authors: Yuh-Tarng
authors: YT
authors: Chen
authors: Hua-Man
authors: HM
authors: Hsu
authors: Li-Jen
authors: LJ
authors: Lee
authors: Shu-Wha
authors: SW
authors: Lin
mesh_terms: D000818:Animals; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D051379:Mice / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C524851:Cul4B protein, mouse; D044842:Cullin Proteins