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Review
. 2015 Nov 26;3:74.
doi: 10.3389/fcell.2015.00074. eCollection 2015.

The Ran Pathway in Drosophila Melanogaster Mitosis

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Free PMC article
Review

The Ran Pathway in Drosophila Melanogaster Mitosis

Jack W C Chen et al. Front Cell Dev Biol. .
Free PMC article

Abstract

Over the last two decades, the small GTPase Ran has emerged as a central regulator of both mitosis and meiosis, particularly in the generation, maintenance, and regulation of the microtubule (MT)-based bipolar spindle. Ran-regulated pathways in mitosis bear many similarities to the well-characterized functions of Ran in nuclear transport and, as with transport, the majority of these mitotic effects are mediated through affecting the physical interaction between karyopherins and Spindle Assembly Factors (SAFs)-a loose term describing proteins or protein complexes involved in spindle assembly through promoting nucleation, stabilization, and/or depolymerization of MTs, through anchoring MTs to specific structures such as centrosomes, chromatin or kinetochores, or through sliding MTs along each other to generate the force required to achieve bipolarity. As such, the Ran-mediated pathway represents a crucial functional module within the wider spindle assembly landscape. Research into mitosis using the model organism Drosophila melanogaster has contributed substantially to our understanding of centrosome and spindle function. However, in comparison to mammalian systems, very little is known about the contribution of Ran-mediated pathways in Drosophila mitosis. This article sets out to summarize our understanding of the roles of the Ran pathway components in Drosophila mitosis, focusing on the syncytial blastoderm embryo, arguing that it can provide important insights into the conserved functions on Ran during spindle formation.

Keywords: Drosophila melanogaster; RanGTP; microtubules; mitosis; mitotic spindle.

Figures

Figure 1
Figure 1
The role of Ran in mitosis. (A) The Drosophila syncytial embryo as a tool for understanding mitosis. In the Drosophila early embryo, the first 13 rounds of mitosis occur rapidly and take place in a shared cytoplasm. Unlike vertebrate cells, which undergo open mitosis and disassemble the nuclear envelope during mitosis, Drosophila undergoes semi-open mitosis, only disassembling the nuclear envelope at the spindle poles. Red, centrosomes; green, MTs; blue, chromosomes. In both vertebrates and Drosophila, Ran.GTP is generated in the vicinity of the chromatin, resulting in a gradient (shown in gray), which is strongest around the chromosomes and weakest at the poles and cortex. (B) Ran mediates mitotic functions via release of Spindle Assembly Factors (SAFs). During mitosis, Ran.GTP is generated around the chromosomes by the chromatin-bound RanGEF RCC1, facilitating the release of SAFs, which are otherwise sequestered by Importins (Imp-β/Imp-α). SAFs have critical roles in, amongst other things, MT anchoring to the kinetochores and centrosomes, in spindle growth from the chromatin, in MT bundling and stabilization, and in anchoring of astral MTs to the cell cortex.
Figure 2
Figure 2
The nuclear transport cycle. During nuclear import, Importins in the cytoplasm recognize and bind to the Nuclear Localization Signal (NLS) of a target protein. The complex of cargo plus the Importin α/β dimer docks at the cytoplasmic side of the nuclear pore and is transported into the nucleus. Subsequently, Ran.GTP in the nucleus binds to Importin β, resulting in disassembly of the complex and releasing the cargo into the nuclear space. Importin α is then recycled back to the cytosol by the Exportin Cellular Apoptosis Susceptibility (Cas) protein via normal Ran-dependent export pathways (Kutay et al., ; Tekotte et al., 2002), while the Importin β/Ran.GTP complex is transported separately (Kose et al., 1999). Upon reaching the cytosolic side of the nuclear envelope, Ran.GTPase Activating Protein 1 (RanGAP1) and Ran Binding Proteins (RanBPs) stimulate Ran-dependent GTP hydrolysis, causing release of Importin β from Ran (Kutay et al., ; Lounsbury and Macara, ; Seewald et al., 2003). RanGAP1 is unable to directly affect Ran.GTP complexed with either importins or exportins, and instead acts via one of several Ran binding proteins (RanBPs) (Bischoff and Görlich, ; Floer et al., ; Kutay et al., ; Lounsbury and Macara, 1997). Nuclear export follows a similar process; Exportins such as chromosome region maintenance 1 (Crm1) recognize and bind to Nuclear Export Signals (NESs) on target proteins. Exportin, Ran.GTP, and cargo form a complex which passes out of the nucleus through the nuclear pore and, as described above (not shown) (Fornerod and Ohno, ; Kuersten et al., 2002). Cytosolic Ran.GDP is transported into the nucleus, where the chromatin-bound Ran guanine exchange factor (RanGEF) RCC1 re-generates a pool of Ran.GTP (Ohtsubo et al., ; Bischoff and Ponstingl, ; Klebe et al., 1995). Thus, the spatial restriction of RanGAP1, RanBPs, and RCC1 results in a large cytoplasmic pool of Ran.GDP and a large nuclear pool of Ran.GTP (Bischoff et al., ; Klebe et al., 1995).

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