Abstract: ABSTRACT Here we we have chosen the regression of the interdigital tissue which sculpts the digits from the hand/foot plate in tetrapod embryos to review the most relevant aspects concerning the regulation and biological significance of programmed cell death. We gather abundant information showing that the initiation of the degenerative process is the result of a complex interplay between the different signaling pathways which are also responsible for limb outgrowth and skeletal tissue differentiation, rather than being regulated by a specific signaling pathway. The model further shows that once the death response is triggered, several different routes of cell disruption, including caspase-dependent apoptosis, lysosomal-mediated cell death, and even a cell senescence process, are activated in the interdigits to ensure their elimination. Transcriptional and structural changes accompanying the degenerative process, and their posible contribution to the control of the death process, are also revised in detail. Finally we survey a number of issues still awaiting clarification, such as the functional implication of interdigital cell death as a source of signals acting on the surrounding tissues, as occurs in the so called “regenerative cell death”.

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