Loss of a Rho-Regulated Actin Nucleator, mDia2, Impairs Cytokinesis during Mouse Fetal Erythropoiesis

Abstract

The small GTPase Rho and mDia2, a Rho-regulated actin nucleator, function as critical regulators of cytokinesis in cultured cells. However, their involvement in cytokinesis during mammalian development remains unknown. Here, we generated mice deficient in mDia2 and examined the role of Rho signaling in cytokinesis during development. mDia2-deficient mice survive until embryonic day 11.5 (E11.5), exhibit severe anemia with multinucleate erythroblasts, and die in utero by E12.5. mDia2-deficient erythroid cells differentiate normally, though in a delayed manner, but exhibit cytokinesis failure with decreased accumulation of F-actin in the cleavage furrow during late differentiation from proerythroblasts. On the other hand, inactivation of Rho induces cytokinesis failure from the earlier progenitor stage. mDia2-deficient erythroblasts, however, are able to enucleate their nuclei. Our findings have thus revealed that mDia2 functions critically in cytokinesis in vivo during erythropoiesis and further suggest that the cytokinesis mechanism in development diverges downstream of Rho. They also demonstrate that cytokinesis and enucleation utilize different mechanisms.

Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation

“…We show that erythroid cells deficient in RhoA often exhibit a multinuclear phenotype indicating failure of cytokinesis. Cytokinesis failure in erythroblasts was also reported recently in a mouse model with germline deletion of mDia2, 42 a formin, which catalyzes the nucleation and polymerization of unbranched actin filaments downstream of Rho GTPases.…”

The formin DIAPH1 (mDia1) regulates megakaryocyte proplatelet formation by remodeling the actin and microtubule cytoskeletons

“…In contrast, DIAPH2 (mDia3) and DIAPH3 (mDia2) are downregulated, possibly to facilitate MK polyploidization and PPF. mDia1 and mDia2 are required for cytokinesis depending on the cell type, [36][37][38] and mDia3 is involved in stabilization of the kinetochores onto spindle microtubules. 39,40 Moreover, mDia2 contributes to the generation of an actin structure that maintains the cortical actin cytoskeleton, 41 and inhibition of mDia2 leads to nonapoptotic membrane blebbing, a process that resembles PPF in MKs.…”

Non-canonical activity of the podosomal formin FMNL1γ supports immune cell migration

“…In this report, we have developed the first murine knockout model of the formin FMNL1. Null mutations of Dia1, Dia2, DAAM1, FHOD3 and FMN1 have resulted in varying degrees of severity, ranging from non-viability to cellular dysfunction (Eisenmann et al, 2007;Kan-O et al, 2012;Li et al, 2011;Watanabe et al, 2013;Zhou et al, 2009). We determined that global depletion of FMNL1 is embryonic lethal; however, targeted depletion of FMNL1 from macrophages provided a model to investigate the functional contributions of FMNL1 in primary macrophages both in vitro and in vivo.…”