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Genome instability and embryonic developmental defects in RMI1 deficient mice.

ABSTRACT: RMI1 forms an evolutionarily conserved complex with BLM/TOP3?/RMI2 (BTR complex) to prevent and resolve aberrant recombination products, thereby promoting genome stability. Most of our knowledge about RMI1 function has been obtained from biochemical studies in vitro. In contrast, the role of RMI1 in vivo remains unclear. Previous attempts to generate an Rmi1 knockout mouse line resulted in pre-implantation embryonic lethality, precluding the use of mouse embryonic fibroblasts (MEFs) and embryonic morphology to assess the role of RMI1 in vivo. Here, we report the generation of an Rmi1 deficient mouse line (hy/hy) that develops until 9.5 days post coitum (dpc) with marked defects in development. MEFs derived from Rmi1(hy/hy) are characterized by severely impaired cell proliferation, frequently having elevated DNA content, high numbers of micronuclei and an elevated percentage of partial condensed chromosomes. Our results demonstrate the importance of RMI1 in maintaining genome integrity and normal embryonic development.

SUBMITTER: Guiraldelli MF

PROVIDER: S-EPMC3797188 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Genome instability and embryonic developmental defects in RMI1 deficient mice.

Guiraldelli Michel F MF Eyster Craig C Pezza Roberto J RJ

DNA repair 20130727 10

RMI1 forms an evolutionarily conserved complex with BLM/TOP3α/RMI2 (BTR complex) to prevent and resolve aberrant recombination products, thereby promoting genome stability. Most of our knowledge about RMI1 function has been obtained from biochemical studies in vitro. In contrast, the role of RMI1 in vivo remains unclear. Previous attempts to generate an Rmi1 knockout mouse line resulted in pre-implantation embryonic lethality, precluding the use of mouse embryonic fibroblasts (MEFs) and embryoni ...[more]

PMID: 23900276

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Project description:BackgroundMaternal obesity is a global issue that has devastating effects across the reproductive spectrum such as meiotic defects in oocytes, consequently worsening pregnancy outcomes. Different studies have shown that such types of meiotic defects originated from the oocytes of obese mothers. Thus, there is an urgent need to develop strategies to reduce the incidence of obesity-related oocyte defects that adversely affect pregnancy outcomes. Multiple growth factors have been identified as directly associated with female reproduction; however, the impact of various growth factors on female fertility in response to obesity remains poorly understood.MethodsThe immature GV-stage oocytes from HFD female mice were collected and cultured in vitro in two different groups (HFD oocytes with and without 50 nM IGF2), however; the oocytes from ND mice were used as a positive control. HFD oocytes treated with or without IGF2 were further used to observe the meiotic structure using different analysis including, the spindle and chromosomal analysis, reactive oxygen species levels, mitochondrial functional activities, and early apoptotic index using immunofluorescence. Additionally, the embryonic developmental competency and embryos quality of IGF2-treated zygotes were also determined.ResultsIn our findings, we observed significantly reduced contents of insulin-like growth factor 2 (IGF2) in the serum and oocytes of obese mice. Our data indicated supplementation of IGF2 in a culture medium improves the blastocyst formation: from 46% in the HFD group to 61% in the HFD + IGF2-treatment group (50 nM IGF2). Moreover, adding IGF2 to the culture medium reduces the reactive oxygen species index and alleviates the frequency of spindle/chromosome defects. We found increased mitochondrial functional activity in oocytes from obese mice after treating the oocytes with IGF2: observed elevated level of adenosine triphosphate, increased mitochondrial distribution, higher mitochondrial membrane potentials, and reduced mitochondrial ultrastructure defects. Furthermore, IGF2 administration also increases the overall protein synthesis and decreases the apoptotic index in oocytes from obese mice.ConclusionsCollectively, our findings are strongly in favor of adding IGF2 in culture medium to overcome obesity-related meiotic structural-developmental defects by helping ameliorate the known sub-optimal culturing conditions that are currently standard with assisted reproduction technologies.

Dataset Information

Genome instability and embryonic developmental defects in RMI1 deficient mice.

Publications

Genome instability and embryonic developmental defects in RMI1 deficient mice.

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