Defective erythroid maturation in gelsolin mutant mice

Background. During late differentiation, erythroid cells undergo profound changes involving actin filaments remodeling. Among proteins controlling actin dynamics is gelsolin (Gsn), a calcium-activated actin filament severing and capping protein. Gelsolin-null mice generated in a C57BL/6 background were viable and fertile1. Design and Methods. We analyzed gelsolin functional roles in erythropoiesis i) by evaluating gelsolin expression in mouse fetal liver cells at different stages of erythroid differentiation (RT-PCR and immunohistochemistry) ii) by characterizing embryonic and adult erythropoiesis in Gsn-/- BALB/c mice (morphology and erythroid cultures). Results. Transferring the Gsn-/- mutation to the BALB/c background causes embryonic lethality. Gsn-/- embryos present defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn-/- mice reaching adulthood fail to recover from PHZ-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays E13.5 fetal livers Gsn-/- cells fail to undergo terminal maturation, a defect partially rescued by cytochalasin D, and mimicked by administration of jasplakinolide to the wt control samples. Conclusions. In BALB/c mice, gelsolin deficiency alters the erythrocyte actin polymerization/depolymerization equilibrium, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn-/- mice lethality observed in mid gestation.