Giet Group Research

The mitotic spindle is a microtubule-based machine required for equal chromosome segregation. This is a key role to maintain genome stability. Spindle assembly defect causes mitotic delay and cell death. Therefore interference with spindle assembly and activation of the spindle checkpoint (SAC) is widely used as a strategy to inhibit cancer cell division.

The mitotic spindle is required for chromosome segregation. In case of spindle assembly defect, the Spindle Assembly Checkpoint remains active and prevent anaphase onset until all chromosomes are correctly attached to perform accurate segregation. If the defects cannot be corrected, the cell can die following long mitotic arrest or can propagate segregation errors, genetic instability and cancer.

The mitotic spindle plays also a crucial role in polarized stem cells to segregate unequally (apical and basal) cell fate determinants in the future daughter cells. This process is important for tissue homeostasis and deregulation 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.

The mitotic spindle is required for asymmetric segregation of cell fate determinants and tissue homeostasis. In stem cells (SCs), the mitotic spindle aligns along the apico basal axis during M phase. Following cytokinesis, the cell basal and apical fate determinants (shown in green and Pink respectively) anchored at the cell cortex are asymmetrically distributed. One cell retains the SC identity (Pink), while the other is committed to differentiation.  Spindle orientation failure triggers symmetric distribution of cell fate determinant and by default, acquisition of the SC fate leading to tumor formation.

Thus, a better understanding of the regulation of the microtubule network would therefore constitute an important advance in order to understand the relationships between abnormal mitotic spindle morphogenesis and cancer. 

Numerous studies 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 first 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 and/or interphasic MAPs, including promising candidate genes required for mitotic spindle assembly. Their contribution for mitotic spindle assembly/alignment and cell division in the CNS of Drosophila melanogaster was assessed using an RNAi-based protocol designed to screen rapidly for these phenotypes. The candidate genes are now analysed in the lab.

Drosophila neural stem cells (Neuroblasts) during metaphase (top) and pro Metaphase (Bottom). Microtubules are red, mitotic chromosomes are green and Atypical Protein Kinase C is blue (Apical cortex) - © E. Gallaud.

Our second goal is to modify spindle shape to investigate the consequences on spindle assembly and orientation. We will ultimately analyse the possible effects for tissue homeostasis.

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