The Effect of Trp53 Gene-Dosage and Parent-of-Origin of Inheritance on Mouse Gamete and Embryo Function In Vitro

摘要

The transformation-related protein 53 (TRP53) has a canonical role as the "guardian of the genome," serving to protect against the propagation of cells with genomic damage. Auto-crine trophic signals act to block the accumulation of TRP53 in the normal preimplantation embryo. Culture of the early embryo at limiting dilutions in simple defined media limits autocrine signaling, resulting in the accumulation of TRP53. This TRP53 reduces the rate of development of embryos. In this study we show that deletion of the Trp53 gene improved development in vitro in a dose-dependent manner. Development to morphological blastocysts increased as the dose of Trp53 was reduced, and this was accompanied by a 7rp53-dependent increase in the allocation of cells to the inner cell mass. The intermediate developmental response of heterozygous mice provides evidence for haploinsufficiency of this trait. This haploinsufficiency was evident irrespective of the parent-of-origin of the null allele; however, zygotes with paternal inheritance of the 7rpJ.3-null allele had better development in vitro than those with maternal inheritance. There was a beneficial effect of the Trp53-null allele on the number of oocytes released by Trp53*f~ females, and heterozygous males produced higher fertilization rates than controls, although this was independent of the genotype of the fertilizing sperm. The study shows that ovulation induction or culture of embryos in limiting conditions creates conditions that favor the early development of embryos inheriting loss of Trp53 function. This occurs even in the heterozygous state, showing that the conditions provide a potential basis for accelerated accumulation of deleterious mutations within a population.