Phenotypic annotation of the mouse X chromosome

Cox, Brian; Vollmer, Marion; Tamplin, Owen J.; Lu, Mi; Biechele, Steffen; Gertsenstein, Marina; Campenhout, Claude Van; Floss, Thomas; Kühn, Ralf; Wurst, Wolfgang; Lickert, Heiko; Rossant, Janet

doi:10.1101/gr.105106.110

Cited by 77 publications

(73 citation statements)

References 43 publications

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“…Here, we generated the Cul4b knockout mice to determine the physiological functions of CUL4B and the pathological basis of CUL4B deficiency in XLMR and the associated developmental defects. While human CUL4B patients can survive to adulthood, Cul4b knockout mice die as early as E7.5, consistent with the observed embryonic lethality upon inactivation of Cul4b by gene trapping [17]. The developmental defects of Cul4b null embryos were attributed exclusively to the degeneration of extra-embryonic tissues, while the epiblast remained largely unaffected by Cul4b deletion.…”

Section: Introductionmentioning

confidence: 49%

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

Liu

Yin

et al. 2012

Cell Res

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Mutations of the CUL4B ubiquitin ligase gene are causally linked to syndromic X-linked mental retardation (XLMR). However, the pathogenic role of CUL4B mutations in neuronal and developmental defects is not understood. We have generated mice with targeted disruption of Cul4b, and observed embryonic lethality with pronounced growth inhibition and increased apoptosis in extra-embryonic tissues. Cul4b, but not its paralog Cul4a, is expressed at high levels in extra-embryonic tissues post implantation. Silencing of CUL4B expression in an extra-embryonic cell line resulted in the robust accumulation of the CUL4 substrate p21 Cip1/WAF and G2/M cell cycle arrest, which could be partially rescued by silencing of p21 Cip1/WAF . Epiblast-specific deletion of Cul4b prevented embryonic lethality and gave rise to viable Cul4b null mice. Therefore, while dispensable in the embryo proper, Cul4b performs an essential developmental role in the extra-embryonic tissues. Our study offers a strategy to generate viable Cul4b-deficient mice to model the potential neuronal and behavioral deficiencies of human CUL4B XLMR patients.

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Section: Introductionmentioning

confidence: 49%

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

Liu

Yin

et al. 2012

Cell Res

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“…Mice gene trap studies indicate that Cul4B loss results in defects in turning and neurulation, as well as shortened posterior axis and stalled cardiac development, resulting in embryonic lethality around embryonic day 9.5 (25). Of par-ticular interest to our studies, there are specific immunologic phenotypes associated with Cul4B mutations.…”

mentioning

confidence: 97%

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

Pfeiffer

Brooks

2012

The Journal of Immunology

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TNF-α is a central mediator of inflammation and critical for host response to infection and injury. TNF-α biosynthesis is controlled by transcriptional and posttranscriptional mechanisms allowing for rapid, transient production. Tristetraprolin (TTP) is an AU-rich element binding protein that regulates the stability of the TNF-α mRNA. Using a screen to identify TTP-interacting proteins, we identified Cullin 4B (Cul4B), a scaffolding component of the Cullin ring finger ligase family of ubiquitin E3 ligases. Short hairpin RNA knockdown of Cul4B results in a significant reduction in TNF-α protein and mRNA in LPS-stimulated mouse macrophage RAW264.7 cells as well as a reduction in TTP protein. TNF-α message t1/2 was reduced from 69 to 33 min in LPS-stimulated cells. TNF-3′ untranslated region luciferase assays utilizing wild-type and mutant TTP-AA (S52A, S178A) indicate that TTP function is enhanced in Cul4B short hairpin RNA cells. Importantly, the fold induction of TNF-α mRNA polysome loading in response to LPS stimulation is reduced by Cul4B knockdown. Cul4B is present on the polysomes and colocalizes with TTP to exosomes and processing bodies, which are sites of mRNA decay. We conclude that Cul4B licenses the TTP-containing TNF-α messenger ribonucleoprotein for loading onto polysomes, and reduction of Cul4B expression shunts the messenger ribonucleoproteins into the degradative pathway.

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“…Whole-mount in situ hybridization and β-galactosidase staining were performed as described (Biechele et al, 2011;Cox et al, 2010). Integrin alpha 4 immunohistochemistry was performed as described (Daane et al, 2011).…”

Section: Postimplantation Embryo Collection Staining and Imagingmentioning

confidence: 99%

Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

et al. 2013

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SUMMARYIn mice and humans the X-chromosomal porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands and thus represents a bottleneck for all Wnt signaling. We have generated a mouse line carrying a floxed allele for Porcn and used zygotic, oocyte-specific and visceral endoderm-specific deletions to investigate embryonic and extra-embryonic requirements for Wnt ligand secretion. We show that there is no requirement for Porcn-dependent secretion of Wnt ligands during preimplantation development of the mouse embryo. Porcn-dependent Wnts are first required for the initiation of gastrulation, where Porcn function is required in the epiblast but not the visceral endoderm. Heterozygous female embryos, which are mutant in both trophoblast and visceral endoderm due to imprinted X chromosome inactivation, complete gastrulation but display chorio-allantoic fusion defects similar to Wnt7b mutants. Our studies highlight the importance of Wnt3 and Wnt7b for embryonic and placental development but suggest that endogenous Porcn-dependent Wnt secretion does not play an essential role in either implantation or blastocyst lineage specification.

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Phenotypic annotation of the mouse X chromosome

Cited by 77 publications

References 43 publications

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

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

Cullin 4B Is Recruited to Tristetraprolin-Containing Messenger Ribonucleoproteins and Regulates TNF-α mRNA Polysome Loading

Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

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