Exit strategy: one that works

Enucleation is the culmination of terminal erythroid differentiation. It results in the release of 2 million new enucleate reticulocytes into your circulation and mine each second. In this issue of Blood, Ubukawa and colleagues shed new light on the mechanism, showing that non-muscle myosin IIb is intimately involved.¹ 

Mammalian red cells and their immediate precursors, reticulocytes, are, unlike their counterparts in some other vertebrates, devoid of nuclei as a result of an “asymmetric” cell division at the final step of terminal erythroid differentiation. Fission of the erythroblast generates the enucleate reticulocyte and a larger moiety in which an extruded nucleus is encased in a plasma membrane (pyrenocyte).²  There has over many years been keen interest in defining the molecular machinery responsible for enucleation and in the similarities and differences between this process and classic cytokinesis, which produces 2 identical daughter cells. By studying and comparing both processes, Ubukawa and colleagues offer new insights into the roles of various cytoskeletal proteins in the 2 cases.

Inhibition of non-muscle myosin II ATPase by blebbistatin blocked both cell division and enucleation, implying its participation in both processes and establishing a previously undefined role for myosin in enucleation. Nonmuscle myosin IIA and myosin IIb are both expressed during terminal erythroid differentiation and while both seem to be involved in cell division, a specific requirement for myosin IIb in enucleation was documented. Moreover, because inhibition of actin polymerization by cytochalasin D blocks both cell division and enucleation, an actomyosin-driven step in enucleation of erythroblasts during terminal erythroid differentiation may be inferred.

Enucleation is a multistep process (see figure) that requires displacement of the nucleus in the erythroblast to one side during the preparatory stage. This is followed by formation of a contractile actin ring, pinching off the nascent reticulocyte from the nucleus, and subsequent redistribution of membrane between the 2 lobes of the dividing cell by vesicle shuttling to restrict the area of contact between the 2 emerging cells.³  The coordinated execution of these diverse events during a period of 8 to 10 minutes requires complex machinery embracing a number of distinct cytoskeletal proteins and signaling interventions. Using specific inhibitors, Ubukawa et al added myosin to the other elements, notably tubulin and actin, found in earlier work to be implicated in enucleation.^4-7  Of course, many questions remain unanswered including the manner of the spatial and temporal assembly of the various components, and we hope that future work using genetic tools and state-of-the-art imaging techniques will provide more comprehensive insights into this fascinating biologic process and also establish a basis for differences between erythropoiesis in mammals and in other vertebrates.

The allure of this topic is due, at least in large measure, to the special physiologic demands that the mature mammalian red cell has evolved to meet. To fulfill the requirements of shape and flexibility, combined with mechanical stability, the nucleated precursor must dispose of its nucleus.⁸  This is a problem that evolution has solved, and that is unique to the erythroid system.