Maternal role for p53 in reproduction

US researchers have discovered that p53, the tumour suppressor protein known as the guardian of the genome, is essential to the successful implantation of embryos in mice.

Arnold J Levine of the Institute for Advanced Study at Princeton University and colleagues chanced upon the discovery following the observation that p53-deficient female mice had significantly lower pregnancy rates than non-deficient female mice.

Male p53-deficient mice seemed to have no such problem, the researchers, whose study appears in the November 29 issue of Nature, report.

Investigating further, they found that p53-deficient female mice had lower levels of LIF (leukaemia inhibitory factor), a cytokine highly expressed at the onset of implantation of the blastocyst in the uterus and essential to its success.

In an accompanying News and Views article, Colin Stewart of the Institute of Medical Biology in Singapore says implantation cannot occur unless epithelial cells lining the uterus are exposed to LIF.

When Levine and colleagues injected p53-deficient mice with LIF at day four of pregnancy, when implantation occurs in mice, normal embryonic implantation rates were observed.

They suggest that p53 may have a similar function in humans.

Stewart says it is not clear why p53, which is usually activated by stress and normally works to protect cells from the consequences of stress-induced DNA damage, has such a major role in regulating LIF in the uterus.

One suggestion could be that because the uterine vascular system changes to prevent hypoxia, or oxygen shortage, during implantation, and hypoxia is one of the stressors that regulates p53 activity, "it is possible that with the evolution of the reproductive system of mammalian females, activation of p53 in response to hypoxia was hijacked to help co-ordinate implantation-associated changes in vascularisation", Stewart writes.

For human females, Levine and colleagues suggest that the modulation of p53 function by certain single nucleotide polymorphisms (SNPs) in the p53 pathway may affect implantation.

"Implantation failure is the most frequent cause of lack of human pregnancy after in vitro fertilisation and embryo transfer," Levine and colleagues write.

"Sufficient uterine LIF protein is an essential condition for implantation, and low LIF levels have been reported in infertile women."

Stewart writes that it would be interesting to see whether these SNPs are linked to cases of unexplained human infertility.