Model of platelet production as suggested by present data and previous studies. As MKs transition from immature cells (A) to released platelets (D), a systematic series of events occurs. (A) MKs develop a highly IMS as they mature. Assembly of the spectrin-based membrane skeleton is involved in the formation of the IMS, providing a membrane reservoir for future formation of proplatelets. (B) Proplatelet production begins with the extension of large pseudopodia that use unique cortical bundles of microtubules to elongate and form thin proplatelet processes with bulbous ends. Proplatelet membranes are lined with a spectrin undercoat. Proplatelet termini contain a bundle of microtubules that loop on themselves. (C) Proplatelet elongation requires the sliding of microtubules past one another, driven by the molecular motor cytoplasmic dynein. As proplatelets elongate, expansion of the membrane surface area requires the outflow of the IMS, a process that likely requires remodeling of the membrane skeleton. Microtubules function as the highways on which mitochondria and granules traffic to the tips of proplatelets. Actin promotes the branching and amplification of proplatelet tips, representing a mechanism to increase the numbers of proplatelet ends, and ultimately, platelets. (D) The entire MK cytoplasm is converted into a mass of proplatelets and preplatelets (anucleate discoid particles 2-10 μm across), which are released from the cell. Preplatelets reversibly convert into barbell proplatelets, a process that is driven by twisting microtubule-based forces. The membrane skeleton stabilizes this barbell form. Platelets release from proplatelet ends after the final fission event. The nucleus is eventually extruded from the mass of proplatelets.