Apoptosis in mammalian preimplantation embryos: regulation by survival factors.

The formation of a developmentally competent mammalian blastocyst requires the transition from a unicellular state, the fertilized zygote, to a differentiated multicellular structure. In common with other developing organisms, generation of the required cell population involves the processes of cell division, differentiation and cell death, all of which can be regulated by peptide growth factors. Cell death in the preimplantation embryo occurs by apoptosis and, by analogy with other systems, may serve to eliminate unwanted cells during the critical developmental transitions that take place during this period. Cells may be eliminated because they are abnormal or possess defects, including damaged DNA or chromosomal abnormalities. At the early cleavage stages, apoptosis may be associated with activation of the embryonic genome and may contribute to the blastomere fragmentation commonly observed in human IVF embryos. The major wave of apoptosis occurs in a number of species in the inner cell mass of the blastocyst, as identified using nuclear labelling including terminal transferase-mediated dUTP nick end labelling (TUNEL) and fluorescence and confocal microscopy. Apoptosis may protect the integrity and cellular composition of the inner cell mass, by eliminating damaged cells or possibly those with an inappropriate phenotype. Preimplantation embryos express genes involved in the regulation and execution of apoptosis and their cells can undergo this default pathway in the absence of exogenous survival signals. Evidence is now accumulating from several species that apoptosis in the embryo is regulated by soluble peptide growth factors acting as survival factors in an autocrine or paracrine manner. To date, these include transforming growth factor alpha and members of the insulin-like growth factor family. Apoptosis may also be affected by environmental factors, including culture conditions and the composition of media. The regulation of apoptosis in the preimplantation embryo is likely to be of critical importance for both embryo viability and for later development, since the cells of the inner cell mass give rise to the fetus and carry the germ line.