Denis and colleagues report on a remarkable phenomenon that destroys conventional wisdom in several respects and greatly extends our understanding of platelet function and biology in general. The platelet, which is an anucleate cell, is generated from the extrusion of megakaryocyte cytoplasm and contains pre-mRNA species (unprocessed transcripts of genes that contain as yet unspliced introns) that should only be found in the nucleus. Further, when a platelet is activated by extrinsic stimuli, it undergoes another process that should be nucleus-specific; platelets use the spliceosome complex (composed of an array of small nuclear RNPs and auxiliary proteins) to remove introns and produce mature mRNA. This mRNA can productively be translated into protein in response to exogenous stimuli, another surprising process in platelets also recently described by Andy Weyrich's laboratory. Interestingly, only a subset of platelet mRNAs contain introns, suggesting the existence of a novel selection process that megakaryocytes use for platelet formation, i.e., choosing selected mRNA as templates for proteins that can be made on demand in response to exogenous stimuli. This remarkable observation adds yet another mechanism to other nuclear independent gene expression pathways including mRNA editing1 and nonsense mediated decay2 . Presumably, this novel series of processes allows platelets to rapidly respond to activating signals by processing primitive mRNAs and making them ready for translation to the peptides, thus bypassing the complexity of mRNA processing and nuclear transport to the cytoplasm. The heretofore unchallenged dogma that transcription of genomic DNA to pre-mRNA and removal of introns by the splicosome complex is nucleus-specific is demolished. The extension of this dogma, that the definite mRNA is transported out to the cytoplasm and the unprocessed intron containing pre-mRNA is degraded in nucleus, is also no longer absolute.
Many questions should soon be answered by follow-up studies. Is this described phenomenon a platelet-specific mechanism, or does a similar mechanism also exist in neutrophils3 and macrophages that have also been shown to synthesize proteins after cytokine or chemokine stimuli? Does it also exist in neuronal outgrowth that share some other structural and functional similarities with megakaryocytes? How does pre-mRNA get out of the nucleus? Do other nuclear-dependent gene-expression mechanisms also take place in platelets and other cells, such as nonsense mediated decay that is also thought to require nuclear component for its initiation2 ? In summary, this elegant, carefully documented work is a beautiful example of the escape from the rigid dogma and adds another previously unforeseen flexibility to generate life complexity. Is this mechanism exaggerated in clonal thrombopoiesis such as polycythemia vera and essential thrombocythemia where thrombosis and bleeding are yet unexplained major causes of morbidity and mortality? There is no doubt that this important work will have practical implications for better understanding thrombosis, hemostasis, and inflammatory conditions wherein platelets play a central role. The remaining questions will have to be unraveled by future studies and other investigators. Sadly, Melvin Denis was an MD/PhD student who did not live to enjoy the publication of this seminal work after losing his life in an avalanche accident.
