Follicular atresia and luteolysis. Evidence of a role for N-cadherin.

Studies suggest that cell-cell interactions may regulate apoptosis; and, in particular, the calcium-dependent cell adhesion molecule N-cadherin has been shown to be capable of modulating this process. Here, we review the evidence that N-cadherin is expressed by human granulosa cells (GCs) and mediates cell-cell adhesion between GCs. There is strong correlation between N-cadherin expression by granulosa or luteal cells and follicular survival in isolated follicles and archival tissue sections. There exists a strong expression of the molecule by GCs in follicles of the resting pool, of growing antral follicles, and of healthy corpora lutea. In contrast, the molecule is lost in degenerating GCs of atretic follicles and in luteal cells of the late luteal phase. Further, the experimental evidence demonstrates that cell-cell adhesion is critical to the survival of GCs and that N-cadherin-mediated cell-cell adhesion is a critical mediator of survival signals and inhibits apoptosis in these cells. Possible mechanisms by which apoptosis may be triggerred in GCs include the downregulation of N-cadherin, which is mediated, at least in part, through the enzymatic cleavage of the extracellular domain of the molecule. Collectively, these observations suggest that downregulation of N-cadherin or the absence of a functional extracellular domain of the molecule prevent GC aggregation and is associated with GC apoptosis. We propose that N-cadherin-mediated GC signaling plays a central role in follicular and luteal cell survival.