Abstract
Tumor suppressor genes are involved in maintaining genome integrity during reproduction (e.g., meiosis). Thus, deleterious alleles in tumor suppressor-deficient mice would exhibit higher mortality during the perinatal period. A recent aging model proposes that perinatal mortality and age-related deleterious changes might define lifespan. This study aimed to quantitatively understand the relationship between reproduction and lifespan using three established tumor suppressor gene (p53, APC, and RECQL4)-deficient mouse strains with the same C57BL/6 background. Transgenic mice delivered slightly reduced numbers of 1st pups than wild-type mice [ratio: 0.81–0.93 (p = 0.1–0.61)] during a similar delivery period, which suggest that the tumor suppressor gene-deficient mice undergo relatively stable reproduction. However, the transgenic 1st pups died within a few days after birth, resulting in a further reduction in litter size at 3 weeks after delivery compared with that of wild-type mice [ratio: 0.35–0.68 (p = 0.034–0.24)] without sex differences, although the lifespan was variable. Unexpectedly, the significance of reproductive reduction in transgenic mice was decreased at the 2nd or later delivery. Because mice are easily affected by environmental factors, our data underscore the importance of defining reproductive ability through experiments on aging-related reproduction that can reveal a trade-off between fecundity and aging and identify RECQL4 as a novel pleiotropic gene.
Highlights
Is promoted in tumor suppressor gene-deficient mice, both higher perinatal mortality and more accumulated damage should shorten the lifespan (Fig. 1B)
Germline meiosis is mediated by genome recombination, and infertility or subfertility is observed in transgenic mice lacking DNA repair genes such as ataxia telangiectasia mutated (ATM), mismatch repair (MMR) genes, retinoblastoma gene (RB)11, p5312–14, and RECQ helicase genes[15]
We performed comparative experiments to assess the reproduction of three independent p 53−/−, APCMin/+, and RECQL4HD/helicase domain (HD) mouse strains by setting the same age at weaning (4 weeks of age) and mating (8 weeks of age) for the mating pairs (Fig. 2B). p53 is considered to be the clearest example of an antagonistically pleiotropic g ene[1], and might serve as a reference for assessing the reproductive ability of tumor suppressor genes in mice
Summary
Is promoted in tumor suppressor gene-deficient mice, both higher perinatal mortality and more accumulated damage should shorten the lifespan (Fig. 1B). We questioned why the mice deficient in the tumor suppressor gene RECQL4 and patients with RTS exhibit a normal lifespan despite showing increased genetic instability[17,21]. We aimed to quantitatively understand the relationship between perinatal mortality and lifespan in three independent well-established tumor suppressor gene-deficient mouse strains To achieve this purpose, we established an experimental procedure with the same environmental conditions to compare and determine the aging-associated fertility of p53−/−, APCMin/+, and RECQL4HD/HD mice with a nearly identical C57BL/6 background (Materials and Methods). We compared the effect of the parental genotype in the selection against deleterious alleles for three independent tumor suppressor genes during development (Fig. 2A) These different transgenic mouse phenotypes might provide generalized information about reproduction in tumor suppressor gene-deficient mice. Because reproductive ability can provide valuable information about transgenic mice, these experiments might contribute to further examination of the aging-related reproductive phenotypes of genetically modified mouse strains generated using newly established technology, including the CRISPR/Cas[9] system
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