Microtubule minus-end depolymerization is a key regulator of mitotic spindle dynamics, chromosome segregation, and primary microcephaly

Diplôme Thèse Microtubule minus-end depolymerization is a key regulator of mitotic spindle dynamics, chromosome segregation, and primary microcephaly eng 2024-10-31 2024-10-31 author Doria Elena 0000-0002-0026-8192 940413 Département de physiologie cellulaire et métabolisme (PHYME) director Meraldi Patrick 0000-0001-9742-8756 108140 Département de physiologie cellulaire et métabolisme (PHYME) 175 10.13097/archive-ouverte/unige:182351 urn:nbn:ch:unige-1823512 Sc. Vie 312 Cell division ensures chromosome segregation into two daughter cells, facilitated by the spindle, a microtubule-based structure. Centrosomes at the spindle poles regulate microtubule nucleation, while chromosomes align at the center. Various proteins tightly control spindle dynamics, including plus-end and minus-end binding proteins, motor proteins, and crosslinkers. Motor proteins drive poleward flux, a conveyor-belt-like movement crucial for chromosome segregation, by sliding bridging microtubules and transmitting force to kinetochore fibers via crosslinkers. The role of minus-end binding proteins in poleward flux regulation has been underexplored. My thesis focuses on WDR62, CAMSAP1, and kinesin-13 family proteins. I discovered that CAMSAP1 protects microtubule minus ends from MCAK-dependent depolymerization and is a precise regulator of poleward flux without affecting spindle architecture or cell division efficiency. Using CAMSAP1 as a tool, we studied correlations between poleward flux defects and the primary microcephaly induced by WDR62 mutations. WDR62 depletion reduces flux speed, while CAMSAP1 depletion increased it; co-depletion restored normal flux speed. These rescues correct chromosomes segregation, reduces the presence of DNA damage markers, and improved cell proliferation, brain size, and cognitive function in a primary microcephaly Drosophila model. CAMSAP1 MCAK WDR62 Microcephaly Lagging chromosomes Dewey 612 134 Département de physiologie cellulaire et métabolisme 21C false 579 Groupe Meraldi Patrick (physiologie cellulaire et métabolisme) 922 86786895-98ec-4022-96c1-d40aebccea90 Thesis Public DoriaElena_thesis_20241312.pdf 6662178 application/pdf Restricted 2025-12-31 632f30e7d464ede610dfe4393688bc9403f64482a3a35db94e12fa355eb93be8 5991a0a7-4c75-4bbd-82f7-030bc0423809 Imprimatur Public IMPRIMATUR_Elena_DORIA_signé_par_to.pdf 190215 application/pdf 40ad0fc241fa371f410eb659af3f2212a6455eef4813ff8b2f9ff3bf732d2a70 openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Microtubule minus-end depolymerization is a key regulator of mitotic spindle dynamics, chromosome segregation, and primary microcephaly				2024	209	264

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