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Please use this identifier to cite or link to this item: http://hdl.handle.net/10277/497

Authors: La Montanara, Paolo
Title: First insights on the signaling pathways related to CDKL5 regulation and on its possible involvement in synaptic plasticity
Abstract: Rett syndrome (RTT) is an X-linked form of mental retardation that occurs sporadically once every 10,000-15,000 female births. After a period of normal development (6-18 months), the patients show a rapid regression of acquired speech and motor skills and the development of several symptoms including mental retardation, seizures, intermittent hyperventilation and stereotypic hand movements. This condition is mainly stable and signs of progressive neurodegeneration are absent. Almost 80% of Rett cases are associated with mutations in the MECP2 (methyl CpG binding protein 2) gene. MeCP2 is a nuclear protein that binds methylated DNA and recruits histone deacetylases and co-repressor complexes to suppress transcription. It belongs to the MBD family of proteins involved in the epigenetic regulation of gene-expression. Recently, mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been found in patients characterized by a subset of Rett clinical phenotypes and generally suffering of infantile spasms and severe mental retardation. The product of CDKL5 is a serine/threonine kinase that belongs to the CMGC family; the exact functions exerted by this kinase and its regulatory mechanisms remain mainly unknown. CDKL5 is present in the nucleus and in the cytosol of neurons and its expression shows a continued increase during development; accordingly, CDKL5 is a critical regulator of neuronal morphogenesis, neurite growth and dendritic arborization. In the cytosol, CDKL5 phosphorylates NGL-1 (Netrin-G1 Ligand 1), a regulator of early synapse formation and maturation. In the nucleus, CDKL5 binds and phosphorylates in vitro MeCP2. Furthermore, in the nucleus CDKL5 colocalizes with nuclear speckles and is probably involved in the regulation of mRNA splicing. Recently our group has demonstrated that the expression levels and the subcellular distribution of CDKL5 are modified by neuronal activation. In particular, a glutamate bath induces in cultured hippocampal neurons the rapid exit of the kinase from the nucleus and its proteasome-dependent degradation. The significance of this response remains to be elucidated. Furthermore, BDNF induces in rat cortical cultures, a rapid phosphorylation of CDKL5. The main aim of this work was to study how neuronal depolarization or activation by BDNF affects Cdkl5 regulation, in terms of gene transcription, post translation modifications of its final protein product and the involved signaling pathway(s). We found that, both in primary murine neuronal cultures and cortical slices, depolarization affects the expression of the gene, both at the transcriptional and post-transcriptional levels, together with its phosphorylation state. The response is affected by the maturation stage of the treated neurons and the involved signaling pathways have been characterized. We speculate that the observed regulation of Cdkl5 during neuronal depolarization could be related to a role of the kinase in neuronal activation. Electrophysiological approaches will be required to confirm the involvement of CDKL5 in the regulation of neuronal activity; furthermore, the identification of novel interactors of Cdkl5 should help in understanding its physiological functions in the central nervous system and the pathological consequences of a malfunctioning CDKL5.
Keywords: CDKL5, kinase, phosphatase, KCl, LTP, LTD
Issue Date: 2013
Language: eng
Doctoral course: Neurobiologia
Academic cycle: 25
Publisher: Università degli Studi dell'Insubria
Citation: La Montanara, P.First insights on the signaling pathways related to CDKL5 regulation and on its possible involvement in synaptic plasticity (Doctoral Thesis, Università degli Studi dell'Insubria, 2013).

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