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Please use this identifier to cite or link to this item: http://hdl.handle.net/10277/841

Authors: Leva, Barbara
Title: Molecular characterization of a Mecp2Y120D mouse model and MeCP2 role in primary cilia formation: implications in Rett syndrome
Abstract: Rett syndrome (RTT) is a neurological progressive disorder affecting about 1/10,000 new born females. Most cases of “classic” RTT are primarily ascribable to sporadic mutations in the X-linked MECP2 gene, encoding the multifunctional methyl-CpG-binding protein 2 (MeCP2). Studies of different mouse models of Mecp2 indicate that MeCP2 activities are modulated by a series of post-translational modifications. We generated a knockin mouse model harboring the human pathogenic tyrosine 120aspartic acid (Y120D) mutation in Mecp2. This mutation was found in a female patient affected by RTT. Studies carried out on Mecp2Y120D mouse line showed a surprisingly severe phenotype overlapping that of Mecp2 null mice. The obtained data showed that the Y120D mutation causes a significant reduction in protein levels of Mecp2 and a clear defect in its chromatin binding. Since our studies on tyrosine 120 phosphorylation allowed us to functionally connect MeCP2 with the centrosome, we investigated whether Mecp2 deficiency might lead to centrosomal dysfunctions also in neurons that represent the most affected cells in RTT. Thus, we undertook a study to determine whether MeCP2 is required for the proper formation of the primary cilium. Our studies demonstrate that loss of MeCP2 determines a defect in ciliogenesis in all tested cells including murine neurons and astrocytes and RTT patients’ fibroblasts. We have also observed a functional defect in the activation of the Sonic Hedgehog pathway. Both morphological and functional defects are rescued by the stabilization of microtubules with an histone deacetylase 6 inhibitor.
Keywords: MeCP2, Rett syndrome, mouse model, chromating binding, primary cilium, ciliogenesis, microtubule instability
Issue Date: 2019
Language: eng
Doctoral course: Medicina sperimentale e traslazionale
Academic cycle: 30
Publisher: Università degli Studi dell'Insubria
Citation: Leva, B.Molecular characterization of a Mecp2Y120D mouse model and MeCP2 role in primary cilia formation: implications in Rett syndrome (Doctoral Thesis, Università degli Studi dell'Insubria, 2019).

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