Synaptic Synthesis, Dephosphorylation, and Degradation

Montanara, Paolo La; Rusconi, Laura; Locarno, Albina; Forti, Lia; Barbiero, Isabella; Tramarin, Marco; Chandola, Chetan; Kilstrup‐Nielsen, Charlotte; Landsberger, Nicoletta

doi:10.1074/jbc.m114.589762

Cited by 31 publications

(10 citation statements)

References 31 publications

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“…We exploited these Mecp2-related phenotypes to understand whether S164 phosphorylation is involved in neuronal maturation. Cultures were assayed at DIV7, when neuronal maturation is progressing and at DIV14, when functional synapses are present 33 . Mecp2- null neurons were infected with lentiviruses expressing the WT or the mutated derivatives of S164; the concomitant expression of GFP from the bicistronic cassette permitted to visualize neuronal morphology ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Stefanelli

Gandaglia

Costa

et al. 2016

Sci Rep

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MeCP2 is a transcriptional regulator whose functional alterations are responsible for several autism spectrum and mental disorders. Post-translational modifications (PTMs), and particularly differential phosphorylation, modulate MeCP2 function in response to diverse stimuli. Understanding the detailed role of MeCP2 phosphorylation is thus instrumental to ascertain how MeCP2 integrates the environmental signals and directs its adaptive transcriptional responses. The evolutionarily conserved serine 164 (S164) was found phosphorylated in rodent brain but its functional role has remained uncharacterized. We show here that phosphorylation of S164 in brain is dynamically regulated during neuronal maturation. S164 phosphorylation highly impairs MeCP2 binding to DNA in vitro and largely affects its nucleosome binding and chromatin affinity in vivo. Strikingly, the chromatin-binding properties of the global MeCP2 appear also extensively altered during the course of brain maturation. Functional assays reveal that proper temporal regulation of S164 phosphorylation controls the ability of MeCP2 to regulate neuronal morphology. Altogether, our results support the hypothesis of a complex PTM-mediated functional regulation of MeCP2 potentially involving a still poorly characterized epigenetic code. Furthermore, they demonstrate the relevance of the Intervening Domain of MeCP2 for binding to DNA.

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Section: Resultsmentioning

confidence: 99%

Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Stefanelli

Gandaglia

Costa

et al. 2016

Sci Rep

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“…The identification of large 3’-UTRs (> 6.6 kb) in the major brain isoforms may suggest additional, previously unrecognised, modes of regulation of CDKL5 . mCdkl5 mRNA has been reported to be present in dendrites in the adult brain where it may have a role in local Cdkl5 synthesis [ 18 ]. It is possible that these large 3’-UTRs may have a role in trafficking Cdkl5 to the dendrites, and it is noticeable that there is a high degree of sequence conservation within this region ( Fig 9 ).…”

Section: Discussionmentioning

confidence: 99%

“…CDKL5 is expressed throughout the cell, including the nucleus and the cytoplasm of the cell soma and dendrites. Studies in cell and animal models have shown that CDKL5 is important for neurite outgrowth and dendritic spine development as well as for functional neuronal plasticity [ 18 – 20 ]. It has also been implicated as an important regulator of cellular responses to oxidative stress [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Characterisation of CDKL5 Transcript Isoforms in Human and Mouse

et al. 2016

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Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3’-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue- and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders.

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“…Mutations in genes involved in the plasticity of synaptic strength are associated with several illnesses (Chao et al, 2007; Fromer et al, 2014; La Montanara et al, 2015). Similarly, sustained exposure to stimuli that drive transmitter switching may contribute to these conditions.…”

Section: Perspectivesmentioning

confidence: 99%

Neurotransmitter Switching? No Surprise

Spitzer¹

2015

Neuron

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Among the many forms of brain plasticity, changes in synaptic strength and changes in synapse number are particularly prominent. However, evidence for neurotransmitter respecification or switching has been accumulating steadily, both in the developing nervous system and in the adult brain, with observations of transmitter addition, loss, or replacement of one transmitter with another. Natural stimuli can drive these changes in transmitter identity, with matching changes in postsynaptic transmitter receptors. Strikingly, they often convert the synapse from excitatory to inhibitory or vice versa, providing a basis for changes in behavior in those cases in which it has been examined. Progress has been made in identifying the factors that induce transmitter switching and in understanding the molecular mechanisms by which it is achieved. There are many intriguing questions to be addressed.

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Synaptic Synthesis, Dephosphorylation, and Degradation

Cited by 31 publications

References 31 publications

Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Characterisation of CDKL5 Transcript Isoforms in Human and Mouse

Neurotransmitter Switching? No Surprise

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