Cytoplasmic aggregation of DDX1 in developing embryos: Early embryonic lethality associated with Ddx1 knockout

Hildebrandt, Matthew R.; Wang, Yixiong; Li, Lei; Yasmin, Lubna; Glubrecht, Darryl; Godbout, Roseline

doi:10.1016/j.ydbio.2019.07.014

Cited by 12 publications

(21 citation statements)

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“…DDX1 is a member of the DEAD box family of RNA binding/unwinding/remodelling proteins 19 . We have previously shown that digestion of 2-cell embryos with RNase A causes disaggregation of DDX1 8 . To further investigate the relationship between RNA and DDX1 vesicles, we used electron microscopy and OsO 4 /uranyl acetate staining which stabilizes nucleic acids and increases electron density 20 .…”

Section: Resultsmentioning

confidence: 99%

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DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos

Wang

Yasmin

et al. 2022

Nat Commun

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The DEAD box protein DDX1, previously associated with 3’-end RNA processing and DNA repair, forms large aggregates in the cytoplasm of early mouse embryos. Ddx1 knockout causes stalling of embryos at the 2-4 cell stages. Here, we identify a DDX1-containing membrane-bound calcium-containing organelle with a nucleic acid core. We show that aggregates of these organelles form ring-like structures in early-stage embryos which we have named Membrane Associated RNA-containing Vesicles. We present evidence that DDX1 is required for the formation of Membrane Associated RNA-containing Vesicles which in turn regulate the spatial distribution of calcium in embryos. We find that Ddx1 knockout in early embryos disrupts calcium distribution, and increases mitochondria membrane potential, mitochondrial activity, and reactive oxygen species. Sequencing analysis of embryos from Ddx1 heterozygote crosses reveals downregulation of a subset of RNAs involved in developmental and mitochondrial processes in the embryos with low Ddx1 RNA. We propose a role for Membrane Associated RNA-containing Vesicles in calcium-controlled mitochondrial functions that are essential for embryonic development.

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Section: Resultsmentioning

confidence: 99%

“…Most embryonic arrests at the 2-cell stage are related to maternal factors. However, a few zygotic genes have also been associated with early embryonic lethality including Pp2cβ 4 , Ddx20 5 , Pfn1 6 , Ercc2 7 and Ddx1 8 . DDX1 is an RNA binding/unwinding protein that is primarily found in the nucleus of somatic cells.…”

Section: Introductionmentioning

confidence: 99%

DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos

Wang

Yasmin

et al. 2022

Nat Commun

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“…*p < .05 with respect to control profile of these three genes was further validated by western blot analysis. HNRNPC, HNRNPU, and RUVBL1 together with DDX1 and HIST1H1C were established chromatin remodelers (Ameyar-Zazoua et al, 2009;Flex et al, 2019;Hildebrandt et al, 2019;Mahajan et al, 2005). HNRNPC is a pleiotropic protein having DNA-damageinduced chromatin-binding during DNA repair and/or damage response, besides its function in RNA metabolism.…”

Section: Discussionmentioning

confidence: 99%

Paternal contributors in recurrent pregnancy loss: Cues from comparative proteome profiling of seminal extracellular vesicles

Jena

Nayak

Kumar

et al. 2020

Molecular Reproduction Devel

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Recent evidence entail paternal factors as plausible contributors in spontaneous recurrent pregnancy loss (RPL). Seminal extracellular vesicles secreted from cells of male reproductive tract carry regulatory proteins and RNAs. They are proposed to regulate sperm maturation and function while their fusion to endometrial stromal cells helps in decidualization. Nevertheless, the mechanism(s) involved in these processes are poorly understood. This study aims at elucidating the molecular basis of paternal contribution by comparative proteomics (label-free LC-MS/MS) of isolated seminal extracellular vesicles from fertile men and partners of patients with RPL (n = 21 per group). Bioinformatics analysis revealed the identified differentially expressed proteins to be involved in DNA replication, recombination and repair, gene expression, cellular assembly and organization, cell death, and survival. Major disease pathways affected were identified as developmental, hereditary, and immunological disorders. Of the three identified hub genes regulating the above disease pathways, two (HNRNPC and HNRNPU) are overexpressed while RUVBL1 is underexpressed along with over expression of HIST1H1C, DDX1, surmising defective chromatin packaging, and histone removal in spermatozoa resulting in improper expression in paternal genes thereby leading to abnormal embryo development. Besides, alteration in GSTP1 expression points oxidative predominance in RPL group. Differential expression of C3, C4a/C4b, CFB, and GDF 15 may be involved in altered maternal immune response to paternal antigens resulting in impaired decidualization.

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“…DDX1 was highly expressed in the developing oocytes and the surrounding granulosa cells of the ovaries. Germline knockout of DDX1 resulted in embryonic lethality in mice ( Hildebrandt et al., 2015 ; Hildebrandt et al., 2019 ). Similarly, our research showed that sjDDX1 silencing affected worm survival and egg laying.…”

Section: Discussionmentioning

confidence: 99%

The Potential Role of MicroRNA‐124‐3p in Growth, Development, and Reproduction of Schistosoma japonicum

Zhou

Hong

Shang

et al. 2022

Front. Cell. Infect. Microbiol.

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The microRNA‐124‐3p plays an important role in regulating development and neurogenesis. Previous microRNA sequencing analyses of Schistosoma japonicum revealed sja-miR-124-3p differential expression patterns in schistosomes from different hosts and at different developmental stages. This study explores the regulatory role of sja-miR-124-3p in S. japonicum development and reproduction. Quantitative reverse-transcription PCR (qRT-PCR) showed that the expression level of sja-miR-124-3p in S. japonicum from resistant hosts, such as Microtus fortis, and unsuitable hosts, such as rats and water buffalo, was significantly higher than that in mice and yellow cattle at the same developmental stage. Overexpressing sja-miR-124-3p in infected mice led to a hepatic egg reduction rate of 36.97%, smaller egg granulomas in the livers, increased liver weight, subsided hepatocyte necrosis, and diminished inflammatory cell infiltration. The width of female worms increased but decreased in males. The vitelline cells were irregular, swollen, or fused. The teguments and ventral sucker of males and females were swollen and broken, but the morphological changes were particularly notable in males. qRT-PCR and dual-luciferase reporter assay system were used to confirm the in-silico-predicted target genes, S. japonicum DEAD-box ATP-dependent RNA helicase 1 (sjDDX1) and DNA polymerase II subunit 2 (sjPOLE2). Our results showed that RNA interference (RNAi)-mediated sjDDX1 silencing in mice provided a 24.55% worm reduction rate and an 18.36% egg reduction rate, but the difference was not significant (p > 0.05). Thus, our findings suggest that sja-miR-124-3p has an important role in growth, development, and reproduction in S. japonicum. All these results will greatly contribute toward providing important clues for searching vaccine candidates and new drug targets against schistosomiasis.

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Cytoplasmic aggregation of DDX1 in developing embryos: Early embryonic lethality associated with Ddx1 knockout

Cited by 12 publications

References 100 publications

DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos

DDX1 vesicles control calcium-dependent mitochondrial activity in mouse embryos

Paternal contributors in recurrent pregnancy loss: Cues from comparative proteome profiling of seminal extracellular vesicles

The Potential Role of MicroRNA‐124‐3p in Growth, Development, and Reproduction of Schistosoma japonicum

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