Proteases of the caspase family represent the central executioners of the apoptotic process. Many recent observations suggest that caspases, beyond their well known main role in cell death, exert important functions in other cellular processes, including cell differentiation and control of T-cell proliferation and cell-cycle progression. Concerning the role of caspases in cell differentiation, recent studies suggest that caspase activation is required for normal keratinocyte differentiation (Weil et al, Current Biol. 1999;9:361-364), for lens fiber differentiation (Ishizaki et al, J Cell Biol. 1998;140:153-158), and for erythroid maturation (Zermati et al, J Exp Med. 2001;193:247-254).
De Botton and colleagues (page 1310) elegantly demonstrate that caspase activation within megakaryocytes is required for platelet production. They present evidence that in vitro–grown megakaryocytes exhibit during their terminal stages of maturation the activation of caspases 3 and 9. Two lines of evidence suggest that this spontaneous caspase activation observed under physiologic conditions is required for platelet production: (1) caspase inhibitors markedly decrease proplatelet formation, and (2) megakaryocytic cells overexpressing the antiapoptotic protein Bcl-2 exhibited reduced proplatelet formation. The most interesting and intriguing finding of this study, however, consisted in the observation that maturing megakaryocytes, before propletelet formation, exhibit a punctuate cytoplasmic distribution of caspase 3, suggesting a localized caspase activation. In contrast, senescent megakaryocytes exhibited a diffuse cytosolic localization. According to these findings, it was proposed that during late megakaryocytic maturation a compartmentalized caspase 3 activation may contribute to proplatelet formation, while at terminal stages of megakaryocytic maturation, in senescent megakaryocytes, caspase activation switches from a localized to a diffuse cytosolic activation with consequent induction of apoptosis.
The role of the localized caspase activation observed during proplatelet formation remains to be defined, at the moment. In this context, it seems reasonable to assume that this localized caspase 3 may contribute to the changes in myosin function and actin cytoskeleton tightly involved in the mechanism of proplatelet formation. The elucidation of the molecular mechanisms responsible for this differential and sequential caspase activation occurring during megakaryocytic maturation will provide a major contribution to the understanding of the mechanisms linking differentiation and apoptosis.
