Factors regulating growth arrest gene expression (gas and gadd) during preimplantation embryogenesis
Genes that are associated with the response of cells to growth arrest and DNA damage include the growth arrest specific (gas) genes, the growth arrest and DNA damage (gadd) genes and the tumour suppressor gene p53. This study was undertaken to characterise the changes in gene expression as the embryo responds to growth arrest. The different types of stress that may be encountered by the embryo in culture, such as amino acid deficiency, DNA damaging agents (MMS and sodium arsenite) and metabolic inhibitors (tunicamycin and PALA), induced different patterns of gene expression. Two different pathways implicated with the negative regulation of growth were identified; one involving the transcriptional activator CHOP-10; the other mediated by arrest in the G1 phase involving p53 and gadd45. Both gadd45 and p53 were expressed in the mouse embryo at the blastocyst-stage, suggesting a role for these genes in a system that arrests growth when embryos are exposed to DNA damage. CHOP-10 was expressed at a constant level from the 8-cell stage onwards and was induced when blastocysts were treated with MMS, the metabolic inhibitor sodium arsenite or an inhibitor or protein glycosylation tunicamycin, but not in blastocysts treated with the inhibitor of nucleotide synthesis PALA. The overexpression of CHOP-10 may be a marker of one of the pathways that lead to apoptosis in the blastocyst. Overall these findings suggest that there is more than one control system regulating growth arrest in the blastocyst and the fetal outcome may differ depending on the type of stress encountered in culture.