Abstract
BackgroundIn standard cell division, the cells undergo karyokinesis and then cytokinesis. Some cells, however, such as cardiomyocytes and hepatocytes, can produce binucleate cells by going through mitosis without cytokinesis. This cytokinesis skipping is thought to be due to the inhibition of cytokinesis machinery such as the central spindle or the contractile ring, but the mechanisms regulating it are unclear. We investigated them by characterizing the binucleation event during development of the Drosophila male accessory gland, in which all cells are binucleate.ResultsThe accessory gland cells arrested the cell cycle at 50 hours after puparium formation (APF) and in the middle of the pupal stage stopped proliferating for 5 hours. They then restarted the cell cycle and at 55 hours APF entered the M-phase synchronously. At this stage, accessory gland cells binucleated by mitosis without cytokinesis. Binucleating cells displayed the standard karyokinesis progression but also showed unusual features such as a non-round shape, spindle orientation along the apico-basal axis, and poor assembly of the central spindle. Mud, a Drosophila homolog of NuMA, regulated the processes responsible for these three features, the classical isoform MudPBD and the two newly characterized isoforms MudL and MudS regulated them differently: MudL repressed cell rounding, MudPBD and MudS oriented the spindle along the apico-basal axis, and MudS and MudL repressed central spindle assembly. Importantly, overexpression of MudS induced binucleation even in standard proliferating cells such as those in imaginal discs.ConclusionsWe characterized the binucleation in the Drosophila male accessory gland and examined mechanisms that regulated unusual morphologies of binucleating cells. We demonstrated that Mud, a microtubule binding protein regulating spindle orientation, was involved in this binucleation. We suggest that atypical functions exerted by three structurally different isoforms of Mud regulate cell rounding, spindle orientation and central spindle assembly in binucleation. We also propose that MudS is a key regulator triggering cytokinesis skipping in binucleation processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-014-0046-5) contains supplementary material, which is available to authorized users.
Highlights
In standard cell division, the cells undergo karyokinesis and cytokinesis
We found that the mitotic wave for binucleation in the main cell population initiated at the middle zone of the accessory gland lobe and propagated to the proximal and distal parts (Additional file 1: Figure S2)
We considered its repression of the central spindle assembly to be a major cause of binucleation because in mud4 hemizygotes, we frequently observed cytokinesis progression even when neither horizontal spindle orientation nor cell rounding was observed (Figure 4B–E and B’– E’) (Additional file 2: Table S1)
Summary
Some cells such as cardiomyocytes and hepatocytes, can produce binucleate cells by going through mitosis without cytokinesis This cytokinesis skipping is thought to be due to the inhibition of cytokinesis machinery such as the central spindle or the contractile ring, but the mechanisms regulating it are unclear. Rho signaling activates effector proteins, such as diaphanous and Rho kinase, that in turn activate the formation of the actin contractile ring that completes cell division by pinching the daughter cells apart [8]. Loss of this cytokinesis machinery results in incomplete cytokinesis and produces binucleate cells [7,9,10]. Recent studies have shown a link between binucleation and inhibition of the cytokinesis machinery in cancer cells [11,12]
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