Spindle assembly checkpoint inactivation fails to suppress neuroblast tumour formation in aurA mutant Drosophila.

Renaud Caous,Roger Karess,Aude Pascal,Régis Giet,Laurent Richard-Parpaillon,Pierre Romé

doi:10.1038/ncomms9879

Abstract

Tissue homeostasis requires accurate control of cell proliferation, differentiation and chromosome segregation. Drosophila sas-4 and aurA mutants present brain tumours with extra neuroblasts (NBs), defective mitotic spindle assembly and delayed mitosis due to activation of the spindle assembly checkpoint (SAC). Here we inactivate the SAC in aurA and sas-4 mutants to determine whether the generation of aneuploidy compromises NB proliferation. Inactivation of the SAC in the sas-4 mutant impairs NB proliferation and disrupts euploidy. By contrast, disrupting the SAC in the aurA mutant does not prevent NB amplification, tumour formation or chromosome segregation. The monitoring of Mad2 and cyclin B dynamics in live aurA NBs reveals that SAC satisfaction is not coupled to cyclin B degradation. Thus, the NBs of aurA mutants present delayed mitosis, with accurate chromosome segregation occurring in a SAC-independent manner. We report here the existence of an Aurora A-dependent mechanism promoting efficient, timed cyclin B degradation.

Highlights

Tissue homeostasis requires accurate control of cell proliferation, differentiation and chromosome segregation
Our results suggest that impaired cyclin B degradation compensates for the defect in chromosome segregation in aurA neural tissues, in the absence of the spindle assembly checkpoint (SAC)
We observed no lagging chromosomes during anaphase and telophase in fixed preparations of tissues from aurA and aurA mad[2] mutants (n440). These findings suggest that mitotic exit and cyclin B degradation were delayed in a SAC-independent manner in aurA mad[2] mutant NBs, and that this delay was sufficient to allow correct attachment of the chromosomes to the spindle before the onset of anaphase

Summary

Introduction

Tissue homeostasis requires accurate control of cell proliferation, differentiation and chromosome segregation. Both daughter cells may become NBs, leading to tumour formation[1,2,3] This is the case for sas-4 mutant flies, which have no centrosomes and display severe spindle orientation defects[4,5]. Wild-type NBs exit mitosis B6–7 min after nuclear envelope breakdown (NEBD), whereas aurA hypomorphic mutant neuroblasts do not exit mitosis until B20 min after NEBD This delay is presumably mediated by prolonged spindle assembly checkpoint (SAC) activation in response to incorrectly attached kinetochores[4,7,12]. We show here that the absence of the SAC in sas-4 mutants strongly impairs chromosome segregation, euploidy and the ability of neural tissues to proliferate and to induce tumours. Our results suggest that impaired cyclin B degradation compensates for the defect in chromosome segregation in aurA neural tissues, in the absence of the SAC

Methods

Results

Conclusion