Expression of alternatively spliced variants of the Dclk1 gene is regulated by psychotropic drugs View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

Magdalena Zygmunt, Dżesika Hoinkis, Jacek Hajto, Marcin Piechota, Bożena Skupień-Rabian, Urszula Jankowska, Sylwia Kędracka-Krok, Jan Rodriguez Parkitna, Michał Korostyński

ABSTRACT

The long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities. Here, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein. In summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments. More... »

PAGES

55

Journal

TITLE

BMC Neuroscience

ISSUE

1

VOLUME

19

From Grant

  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s12868-018-0458-4

    DOI

    http://dx.doi.org/10.1186/s12868-018-0458-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1106943356

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30208879


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    JSON-LD is a popular format for linked data which is fully compatible with JSON.

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    N-Triples is a line-based linked data format ideal for batch operations.

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1186/s12868-018-0458-4'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1186/s12868-018-0458-4'

    RDF/XML is a standard XML format for linked data.

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