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During mitotic entry, the spatial and temporal regulation of the microtubule network is crucial for mitotic spindle assembly and cell division. Defects in spindle assembly are detected by the “spindle assembly checkpoint” (SAC) that remains active in case of defective attachment of microtubules to the kinetochores. During interphase, the microtubule network also plays key roles as it orchestrates intracellular transport, a process required for polarity and morphogenesis. It is thus of crucial importance to understand how microtubule dynamics and polarised transport are regulated and coordinated to regulate cell division and morphogenesis. Our main project is to identify key components of the microtubule network (Microtubule-Associated Proteins, MAPs) by combination of biochemistry and proteomics. We propose to analyse the contribution of these MAPs for SAC activation, as well as their roles in morphogenesis using Drosophila melanogaster, a model system in which we can screen for genes required for these 2 processes.
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The mitotic spindle is a microtubule-based machine required for equal chromosome segregation, a key role to maintain genome stability. Spindle assembly defect causes mitotic delay or cell death. Therefore interference with spindle assembly and activation of the spindle checkpoint is widely used as a strategy to inhibit (cancer) cell division (fig.1).
The mitotic spindle plays also a crucial role in polarized stem cells to define the plan of cell division and thus to segregate unequally cell fate determinants in the future daughter cells. This process is important for tissue homeostasis and may be the cause of tumor formation. Indeed, mitotic spindle orientation failure along the apico-basal axis triggers missegregation of cortical cell fates and overproliferation (fig.2). Thus, a better understanding of the regulation of the microtubule network regulation by Microtubule Associated proteins (MAPS) would therefore constitute an important advance in order to understand the relationships between mitotic spindle morphogenesis and cancer.
 
<gallery widths=500px heights=200px  perrow=0 >
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Image:SpindleGiet.jpg|[[Media:SpindleGiet.jpg|Fig.1: The mitotic spindle is required for chromosome segregation.(click to enlarge)]]
Image:Asymdivgiet.jpg|[[Media:Asymdivgiet.jpg|Fig.2: The mitotic spindle is required to segregate cell fate determinants.(click to enlarge)]]
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Numerous studies in the literature have shown that the morphological changes of the microtubule arrays are regulated by the direct association/dissociation of Microtubule Associated Proteins (MAPs) with the microtubules. The aim of our project is to identify new MAPs required for the assembly and/or the orientation of the mitotic spindle. Using a differential screening method, we have been able to specifically isolate mitotic “MAPs” (fig.3), including promising candidate genes required for mitotic spindle assembly. Their contribution for mitotic spindle assembly/alignment, cell division in the CNS of Drosophila melanogaster was assessed using an RNAi-based protocol designed to screen rapidly for these phenotypes (fig.4). We are now studying candidate genes individually.
 
<gallery widths=500px heights=200px  >
Image:Fig1ABCGiet.jpg|[[Media:Fig1ABCGiet.jpg|Fig.3: Isolation of mitotic MAPs. (click to enlarge)]]
Image:Fig4Giet.jpg|[[Media:Fig4Giet.jpg|Fig.4: Mitotic Neuroblasts following RNAi directed against several known (klp61F,polo) and putative new mitotic genes identified in this study (CG2943=Tcp-1,CG14998=Ensconsin). (click to enlarge)]]
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Revision as of 06:50, 15 July 2014

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The mitotic spindle is a microtubule-based machine required for equal chromosome segregation, a key role to maintain genome stability. Spindle assembly defect causes mitotic delay or cell death. Therefore interference with spindle assembly and activation of the spindle checkpoint is widely used as a strategy to inhibit (cancer) cell division (fig.1). The mitotic spindle plays also a crucial role in polarized stem cells to define the plan of cell division and thus to segregate unequally cell fate determinants in the future daughter cells. This process is important for tissue homeostasis and may be the cause of tumor formation. Indeed, mitotic spindle orientation failure along the apico-basal axis triggers missegregation of cortical cell fates and overproliferation (fig.2). Thus, a better understanding of the regulation of the microtubule network regulation by Microtubule Associated proteins (MAPS) would therefore constitute an important advance in order to understand the relationships between mitotic spindle morphogenesis and cancer.

Numerous studies in the literature have shown that the morphological changes of the microtubule arrays are regulated by the direct association/dissociation of Microtubule Associated Proteins (MAPs) with the microtubules. The aim of our project is to identify new MAPs required for the assembly and/or the orientation of the mitotic spindle. Using a differential screening method, we have been able to specifically isolate mitotic “MAPs” (fig.3), including promising candidate genes required for mitotic spindle assembly. Their contribution for mitotic spindle assembly/alignment, cell division in the CNS of Drosophila melanogaster was assessed using an RNAi-based protocol designed to screen rapidly for these phenotypes (fig.4). We are now studying candidate genes individually.




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