Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis

Liu, Liren; Yin, Yan; Li, Yuewei; Prevedel, Lisa; Lacy, Elizabeth; Ma, Liang; Zhou, Pengbo

doi:10.1038/cr.2012.48

Cited by 56 publications

(68 citation statements)

References 39 publications

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“…Mice-Generation of conditional Cul4b mice was described previously (7). The Vasa(Ddx4)-Cre (stock no.…”

Section: Methodsmentioning

confidence: 99%

“…Here we investigate the role of Cul4b in murine spermatogenesis. Our previous studies showed that Cul4b mutant mouse embryos died in midgestation because of a G 2 /M arrest in extraembryonic tissues, whereas epiblast-specific null mutants survived to adulthood with no overt developmental defects (7). To investigate the role of CUL4B protein in mammalian spermatogenesis, we generated and characterized germ cell-specific as well as global Cul4b mutant mice.…”

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confidence: 99%

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Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis

Yin¹,

Liu

Yang

et al. 2016

Journal of Biological Chemistry

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CUL4B ubiquitin ligase belongs to the cullin-RING ubiquitin ligase family. Although sharing many sequence and structural similarities, CUL4B plays distinct roles in spermatogenesis from its homologous protein CUL4A. We previously reported that genetic ablation of Cul4a in mice led to male infertility because of aberrant meiotic progression. In the present study, we generated Cul4b germ cell-specific conditional knock-out (Cul4b Protein degradation via the ubiquitin-proteasome system plays a critical role during mammalian spermatogenesis. Timely removal of outlived proteins is crucial to ensure progression through different phases of spermatogenesis including mitotic, meiotic divisions, and postmeiotic morphogenesis. The ubiquitin-proteasome system selects its targets via a group of E3 ubiquitin ligases, which upon interaction with E2 ubiquitin-conjugating enzymes tag substrates for proteasomal degradation by the 26S proteasome. The largest mammalian E3 ligase family is the CRL (cullin-RING finger ubiquitin ligase) family, which includes eight members. Each cullin family member serves as a molecular scaffold and forms an E3 ligase complex with substrate-recruiting receptors and a linker protein (1). The Cul4b gene, located on the X chromosome, shares extensive sequence homology and functional redundancy with the other CRL4 family member, Cul4a. Both proteins employ DDB1 (DNA damage-binding protein 1) as the linker protein, which in turn recruits common or distinct DDB1-CUL4 associated factors for substrate binding. The DDB1-CUL4-mediated protein modification/degradation is involved in critical cellular processes including DNA replication, DNA repair, cell cycle control, and histone modifications (2).Male infertility accounts for ϳ40 -50% of infertility cases in humans (3, 4). Many factors contribute to male infertility; however, the vast majority of male infertility cases are associated with oligozoospermia (decreased sperm number), asthenozoospermia (reduced sperm motility), and/or teratozoospermia (abnormal sperm morphology). In the mammalian testis, a single pluripotent spermatogonial stem cell (SSC) 2 undergoes several rounds of mitotic divisions followed by meiotic divisions and complex postmeiotic morphogenesis, eventually giving rise to a cohort of mature spermatozoa. We have previously reported that the CRL4 proteins exhibited complementary expression patterns in adult mouse testis, where CUL4A was predominantly detected in primary spermatocytes, whereas CUL4B was highly expressed in Sertoli cells, spermatogonia, and spermatids (5). The absence of CUL4B in spermatocytes is likely due to meiotic sex chromosome inactivation, a transient X chromosome inactivation caused by sex chromosome condensation and subsequent gene silencing (6). However, the

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“…Mice-Generation of conditional Cul4b mice was described previously (7). The Vasa(Ddx4)-Cre (stock no.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis

Yin¹,

Liu

Yang

et al. 2016

Journal of Biological Chemistry

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“…CUL4A, CUL4B, and Cdt2 Knockdown Cell Lines-Human CUL4A, CUL4B shRNA, and control shRNA were as described previously (47,48). Human Cdt2-shRNA (mature sense sequence, GGTTATCAGTGCAGTGGT) was obtained from Open Biosystems.…”

Section: Methodsmentioning

confidence: 99%

“…Examples of where one or the other CUL4 genes exhibit predominant roles are in the regulation of DDB2 and p21 in mouse epithelial cells by CUL4A, and in mouse models where CUL4A is essential for spermatogenesis and male fertility (59). Deficiency of CUL4B is associated with syndromic X-linked mental retardation in humans (60), and mice with targeted disruption of CUL4B show that it has an essential role in extra-embryonic tissue development during embryogenesis (48).…”

Section: Cdt2mentioning

confidence: 99%

A Novel Function of CRL4Cdt2

Zhang

Zhao

Darzynkiewicz

et al. 2013

Journal of Biological Chemistry

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“…In the most recent study published in Cell Research, Zhou and coworkers [12] attempted to generate conditional Cul4b knockout mice with targeted deletion of Cul4b at exons 4 and 5, giving rise to a non-functional Cul4b fragment lacking both the DDB1-binding domain and the cullin homology domain for RBX1 recruitment. The chicken-actin (CAG)-Cre was used, which drives Cre-mediated recombination at the early zygote stage, leading to Cul4b deletion in both the embryo proper and extraembryonic tissues.…”

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confidence: 99%