Cell death/apoptosis: normal, chemically induced, and teratogenic effect

Cell death is an integral part of a variety of biological processes including cell proliferation, differentiation, and morphogenesis. We review here the morphological and biochemical nature as well as the genetic basis for cell death during normal and abnormal development. Most often referred to in normal development as programmed cell death, this controlled process determines the size, patterning, and function of many tissues. The importance of its proper genetic regulation is demonstrated by the discovery of cell death-specific genes and the several disorders including cancer and teratogenesis that result from repression or enhancement of cell death. In our studies we employed the developing mouse limb, which provides a defined window of active cell death, to elucidate mechanisms of cell death. We have developed markers that reveal in the developing normal limb an apoptotic morphology with phagocytosis and DNA fragmentation. In the limb deformity mutant Hammertoe there is a defective (restricted) cell death pattern, but the morphology remains apoptotic. By the use of these markers, we were able to observe that the teratogen retinoic acid produced enhanced apoptotic cell death. Most interestingly, retinoic acid-induced cell death in the Hammertoe mutant resulted in correction of the mutant phenotype. Future studies will determine the relationship between exogenous agents and endogenous signaling pathways as well as indicate how these interactions can alter the fate of a given cell and potentially ameliorate a genetic abnormality.