The Role of Microtubule nucleation during neural development
[eng] The γ-‐tubulin ring complex (γTuRC) is required to efficiently generate new microtubules (MT) in a process known as MT nucleation. In mitotic cells, MT nucleation by γTuRC occurs from the centrosome, in vicinity of the chromosomes and from the lattice of pre-‐ existing MTs in a process addit...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/148548 |
| Acceso en línea: | https://hdl.handle.net/2445/148548 http://hdl.handle.net/10803/668349 |
| Access Level: | acceso abierto |
| Palabra clave: | Neurobiologia del desenvolupament Cervell Neurones Microtúbuls Nucleació Developmental neurobiology Brain Neurons Microtubules Nucleation |
| Sumario: | [eng] The γ-‐tubulin ring complex (γTuRC) is required to efficiently generate new microtubules (MT) in a process known as MT nucleation. In mitotic cells, MT nucleation by γTuRC occurs from the centrosome, in vicinity of the chromosomes and from the lattice of pre-‐ existing MTs in a process additionally involving the augmin complex. In neurons, the centrosome loses its MT nucleation capacity, while the γTuRC can still promote nucleation elsewhere. Still, it remains unclear how the γTuRC is regulated in these cells and whether other non-‐centrosomal sites function as microtubule-‐organizing centre in neurons. The aim of this thesis is to understand how MT nucleation mediated by augmin and γTuRC contributes to brain development and how nucleation is regulated during this process. In this thesis we show that the augmin complex is required for both axonal and dendritic development in vitro. In the axon, augmin guarantees that MTs are nucleated with the correct orientation, ensuring uniform axonal MT polarity. On the other hand, augmin depletion leads to an overall decrease in MT density in dendrites with no major effect on their polarity. Surprisingly, despite our findings, analysis of augmin function by other groups in vivo in flies and zebrafish has not revealed any dramatic defects. Strikingly, we show that, in conditional KO mice with gene deletion in the augmin subunit Haus6 in neural progenitors, brain development is halted before embryonic day 13 and the animals die at birth. These major brain defects are caused by impaired mitosis and massive cell death in neuroprogenitors, indicating significant, species-‐specific differences in the requirement for augmin function. In the last part of this thesis we identified KIF2A and CEP170 as γTuRC interactors in in vitro cultured mouse cortical neurons and we show that, in agreement with published data on KIF2A function, CEP170 seems to inhibit growth of axon collateral branches. We speculate that KIF2A and CEP170 may function as negative regulators of microtubules nucleation by γTuRC. Together these results establish augmin-‐mediated nucleation as essential for mammalian brain development and provide first insight in the regulation of microtubule nucleation in neurons by γTuRC interactors. |
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