A genetic analysis on a novel regulatory mechanism to induce cell death in response to perturbation of dynamic instability of microtubules

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Microtubules are indeed involved in many cellular phenomena. It has been shown that dynamic instability of microtubules is especially important for regulation of some cellular events. The Orbit/CLASP, a conserved microtubule-associated protein enriched at plus-ends of microtubules plays an essential role in regulation of the dynamic instability. Loss-of-function mutations of the orbit in Drosophila increase instability of microtubules. Conversely, over-expression of the gene in imaginal discs using GAL4-UAS system causes excessive stabilization of microtubules and consequently a formation of microtubule bundles that are never observed in normal cells at interphase. The over-expression of the orbit in eye disc cells after morphogenic furrows accumulates metaphase cells, suggesting it activates the microtubule assembly checkpoint in mitosis. We found that the over-expression eventually induces apoptosis dependent on Caspase 3 at post-mitotic stage in the eye discs. Knockdown of the gene also causes induction of the Caspase 3 in wing discs. This type of apoptosis cannot be observed in non-dividing cells such as larval salivary gland cells with over-expression of the orbit. The induction of apoptosis is required for a proper function of mitotic checkpoint genes and p53. Our data should suggest that cells with abnormal microtubules deviated from proper range of the dynamic instability could be recognized during mitosis and could be eliminated by the apoptosis from proliferating tissues.