RED CELLS , IRON , AND ERYTHROPOIESIS Tropomodulin 3-null mice are embryonic lethal with anemia due to impaired erythroid terminal differentiation in the fetal liver

Biogenesis of mammalian red blood cells (RBCs) is a complex morphogenetic process of coordinated gene expression, proliferation, and terminal differentiation, with the final stages involving nuclear condensation and cell-cycle exit coordinated with nuclear polarization and expulsion. During nuclear polarization and expulsion, RBC membrane proteins are retained with the nascent reticulocyte, while unwanted proteins are sorted to the membrane overlying the expelled nucleus. Erythroblast enucleation has been likened to a form of asymmetric cell division, based on cell polarity signals contributed by microtubules, filamentous actin (F-actin), and myosin IIB assembly into a contractile ring-like structure at the constriction site between the extruding nucleus and the nascent reticulocyte. Similar to cytokinesis, F-actin assembly stimulated by Rac GTPases and a downstream effector, mDia2 (an F-actin–nucleating formin-homology protein), are required for enucleation of mouse erythroblasts. Inhibition of myosin IIB activity and filament assembly also reduces enucleation in mouse and human erythroblast cultures. Other studies implicate actin-regulated membrane trafficking of late endosomes and membrane remodeling as drivers of enucleation. With the exception of Rac GTPases, mDia2, and myosin II, the factors responsible for actin cytoskeleton remodeling during enucleation are not known. Actin cytoskeleton regulation may also contribute to erythroblast enucleation via interactions of erythroblasts with macrophages. Erythroblasts differentiate in association with a large central macrophage to form erythroblastic islands in the bonemarrow and fetal liver during embryonic development. Studies of fetal liver erythropoiesis show that erythroblast differentiation, survival, and enucleation depend on erythroblast-macrophage adhesion receptor interactions, andmacrophage phagocytosis of extruded nuclei, processes that require the actin cytoskeleton. To date, palladin inmacrophages is the only F-actin binding protein shown to be required for erythroblastic island formation. Tmods bind to tropomyosins and cap the pointed ends of actin filaments to regulate their length and stability. The Tmod family consists of four Tmods, with Tmod1 being the sole Tmod in human and mouse RBCs, where it caps the short actin filaments in the spectrin-actin network of the membrane skeleton. Tmod1-null mice display a mild compensated, sphero-elliptocytic anemia with