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Please use this identifier to cite or link to this item: http://hdl.handle.net/10277/644

Authors: Barbiero, Isabella
Title: A novel role of CDKL5 in the regulation of mitotic spindle assembly and microtubule organization.
Abstract: Mutations in the CDKL5# gene, located on Xp22, are the main cause of CDKL56 disorder characterized by the onset of epilepsy before 3 months of age, severe developmental delay and RTT6like features. Besides its functions in post6mitotic neurons, a recent work shows that the loss of CDKL5 influences the proliferation rate of neuronal precursors suggesting its role also in proliferating cells. However, the molecular mechanism through which CDKL5 acts on this cellular process is still unknown. In this study we demonstrate the presence of CDKL5 at the mitotic centrosome and midbody. Importantly, the ablation of CDKL5 induces prolonged prometaphases, aberrant/multipolar spindle assembly and misaligned chromosomes. Furthermore, we show that, similar to many centrosomal proteins, CDKL5 influences microtubule organization. At the molecular level, we find that CDKL5 interacts with the scaffold protein IQGAP1, a regulator of Rac1, which regulates many cytoskeleton functions thanks to its ability to interact both with actin and plus end microtubule binding proteins (+TIPs). CDKL5 is required for the correct localization of IQGAP1 at the leading edge of polarized cells and down6regulation of CDKL5 reduces the capacity of IQGAP1 to interact with its effector proteins Rac1 and CLIP170, a +TIP that promotes microtubule stabilization at the cell cortex. Altogether, our data suggest that CDKL5 influences cell cycle progression through its centrosomal accumulation and cellular morphology through its interaction with microtubule associated proteins. We believe that these data will pave the way for a further understanding of the impact of CDKL5 in neuronal and non6neuronal cells
Keywords: CDKL5, IQGAP1, centrosome, microtubules
Issue Date: 2015
Language: eng
Doctoral course: Neurobiologia
Academic cycle: 28
Publisher: Università degli Studi dell'Insubria
Citation: Barbiero, I.A novel role of CDKL5 in the regulation of mitotic spindle assembly and microtubule organization. (Doctoral Thesis, Università degli Studi dell'Insubria, 2015).

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