CELL DEATH APOPTOSIS - NORMAL, CHEMICALLY-INDUCED, AND TERATOGENIC EFFECT/

Cell death is an integral part of a variety of biological processes in cluding cell proliferation, differentiation, and morphogenesis. We rev iew here the morphological and biochemical nature as well as the genet ic basis for cell death during normal and abnormal development. Most o ften referred to in normal development as programmed cell death, this controlled process determines the size, patterning, and function of ma ny tissues. The importance of its proper genetic regulation is demonst rated by the discovery of cell death-specific genes and the several di sorders including cancer and teratogenesis that result from repression or enhancement of cell death. In our studies we employed the developi ng mouse limb, which provides a defined window of active cell death, t o elucidate mechanisms of cell death. We have developed markers that r eveal in the developing normal limb an apoptotic morphology with phago cytosis and DNA fragmentation. In the limb deformity mutant Hammertoe there is a defective (restricted) cell death pattern, but the morpholo gy remains apoptotic. By the use of these markers, we were able to obs erve that the teratogen retinoic acid produced enhanced apoptotic cell death. Most interestingly, retinoic acid-induced cell death in the Ha mmertoe mutant resulted in correction of the mutant phenotype. Future studies will determine the relationship between exogenous agents and e ndogenous signaling pathways as well as indicate how these interaction s can alter the fate of a given cell and potentially ameliorate a gene tic abnormality. (C) 1997 Elsevier Science B.V.