Early pre-implantation lethality in mice carrying truncated mutation in the RNA polymerase 1-2 gene

Chen, Hui; Li, Zhenghua; Haruna, Kyoko; Li, Zhengzhe; Li, Zhongzhe; Semba, Kei; Araki, Masatake; Yamamura, Ken Ichi; Araki, Kimi

doi:10.1016/j.bbrc.2007.11.019

Cited by 28 publications

(32 citation statements)

References 25 publications

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“…Emg1- null mutants exhibit arrested development prior to the blastocyst stage, similar to that observed in other mouse models that lack factors involved in ribosomal RNA synthesis or processing, including RBM19 (RNA-binding motif protein 19) [18], pescadillo-1 (PES-1) [19], fibrillarin [20], RNA polymerase I or II [21], BYSL [22], SURF6 [23] and RPS19 (ribosomal protein S19) [24]. Some of these genetic mutations have been clearly demonstrated to cause severe defects in ribosomal biogenesis [19,21,22]. Thus, loss of EMG1 function in mice could also disrupt this biological pathway, leading to pre-implantation lethality.…”

Section: Resultssupporting

confidence: 63%

EMG1 is essential for mouse pre-implantation embryo development

Sandhu

Patel

et al. 2010

BMC Dev Biol

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BackgroundEssential for mitotic growth 1 (EMG1) is a highly conserved nucleolar protein identified in yeast to have a critical function in ribosome biogenesis. A mutation in the human EMG1 homolog causes Bowen-Conradi syndrome (BCS), a developmental disorder characterized by severe growth failure and psychomotor retardation leading to death in early childhood. To begin to understand the role of EMG1 in mammalian development, and how its deficiency could lead to Bowen-Conradi syndrome, we have used mouse as a model. The expression of Emg1 during mouse development was examined and mice carrying a null mutation for Emg1 were generated and characterized.ResultsOur studies indicated that Emg1 is broadly expressed during early mouse embryonic development. However, in late embryonic stages and during postnatal development, Emg1 exhibited specific expression patterns. To assess a developmental role for EMG1 in vivo, we exploited a mouse gene-targeting approach. Loss of EMG1 function in mice arrested embryonic development prior to the blastocyst stage. The arrested Emg1-/- embryos exhibited defects in early cell lineage-specification as well as in nucleologenesis. Further, loss of p53, which has been shown to rescue some phenotypes resulting from defects in ribosome biogenesis, failed to rescue the Emg1-/- pre-implantation lethality.ConclusionOur data demonstrate that Emg1 is highly expressed during mouse embryonic development, and essential for mouse pre-implantation development. The absolute requirement for EMG1 in early embryonic development is consistent with its essential role in yeast. Further, our findings also lend support to the previous study that showed Bowen-Conradi syndrome results from a partial EMG1 deficiency. A complete deficiency would not be expected to be compatible with a live birth.

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Section: Resultssupporting

confidence: 63%

EMG1 is essential for mouse pre-implantation embryo development

Sandhu

Patel

et al. 2010

BMC Dev Biol

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“…This is soon after the onset of rDNA transcription and suggests that the maternal ribosome pool is limiting for development beyond this stage. Consistent with this, embryos carrying homozygous deletions of the genes encoding the second largest subunit of RPI [55] and the processome component Fibrillarin [56] also arrest development at this stage. In stark contrast, homozygous deletion of the gene for RPI initiation factor Rrn3/TIF1A was found to arrest development at 7.5–9.5 dpc [57], by which stage the ribosome content of the embryo is many thousands of times the maternal component.…”

Section: Discussionsupporting

confidence: 60%

Conditional Inactivation of Upstream Binding Factor Reveals Its Epigenetic Functions and the Existence of a Somatic Nucleolar Precursor Body

et al. 2014

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Upstream Binding Factor (UBF) is a unique multi-HMGB-box protein first identified as a co-factor in RNA polymerase I (RPI/PolI) transcription. However, its poor DNA sequence selectivity and its ability to generate nucleosome-like nucleoprotein complexes suggest a more generalized role in chromatin structure. We previously showed that extensive depletion of UBF reduced the number of actively transcribed ribosomal RNA (rRNA) genes, but had little effect on rRNA synthesis rates or cell proliferation, leaving open the question of its requirement for RPI transcription. Using gene deletion in mouse, we now show that UBF is essential for embryo development beyond morula. Conditional deletion in cell cultures reveals that UBF is also essential for transcription of the rRNA genes and that it defines the active chromatin conformation of both gene and enhancer sequences. Loss of UBF prevents formation of the SL1/TIF1B pre-initiation complex and recruitment of the RPI-Rrn3/TIF1A complex. It is also accompanied by recruitment of H3K9me3, canonical histone H1 and HP1α, but not by de novo DNA methylation. Further, genes retain penta-acetyl H4 and H2A.Z, suggesting that even in the absence of UBF the rRNA genes can maintain a potentially active state. In contrast to canonical histone H1, binding of H1.4 is dependent on UBF, strongly suggesting that it plays a positive role in gene activity. Unexpectedly, arrest of rRNA synthesis does not suppress transcription of the 5S, tRNA or snRNA genes, nor expression of the several hundred mRNA genes implicated in ribosome biogenesis. Thus, rRNA gene activity does not coordinate global gene expression for ribosome biogenesis. Loss of UBF also unexpectedly induced the formation in cells of a large sub-nuclear structure resembling the nucleolar precursor body (NPB) of oocytes and early embryos. These somatic NPBs contain rRNA synthesis and processing factors but do not associate with the rRNA gene loci (NORs).

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“…Furthermore, we observe reduction of both intron-containing and single-exon transcripts, indicating that the global reduction is not due to a failure of pre-mRNA splicing which has also been shown required for blastocyst formation [36], [37]. Similarly, RNA polymerase I deficient embryos develop to morula but fail to form blastocysts [38], supporting the possibility that Wdr74 is an essential component of RNA polymerase complexes.…”

Section: Discussionsupporting

confidence: 70%

Wdr74 Is Required for Blastocyst Formation in the Mouse

et al. 2011

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Preimplantation is a dynamic developmental period during which a combination of maternal and zygotic factors program the early embryo resulting in lineage specification and implantation. A reverse genetic RNAi screen in mouse embryos identified the WD Repeat Domain 74 gene (Wdr74) as being required for these critical first steps of mammalian development. Knockdown of Wdr74 results in embryos that develop normally until the morula stage but fail to form blastocysts or properly specify the inner cell mass and trophectoderm. In Wdr74-deficient embryos, we find activated Trp53-dependent apoptosis as well as a global reduction of RNA polymerase I, II and III transcripts. In Wdr74-deficient embryos blocking Trp53 function rescues blastocyst formation and lineage differentiation. These results indicate that Wdr74 is required for RNA transcription, processing and/or stability during preimplantation development and is an essential gene in the mouse.

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Early pre-implantation lethality in mice carrying truncated mutation in the RNA polymerase 1-2 gene

Cited by 28 publications

References 25 publications

EMG1 is essential for mouse pre-implantation embryo development

EMG1 is essential for mouse pre-implantation embryo development

Conditional Inactivation of Upstream Binding Factor Reveals Its Epigenetic Functions and the Existence of a Somatic Nucleolar Precursor Body

Wdr74 Is Required for Blastocyst Formation in the Mouse

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