Biology subjects

Wimberger, P.

Publications and source records attributed to Wimberger, P..

3 recordsLinked to original sources

bioRxiv2018

Hypoxia-induced epigenetic silencing of polo-like kinase 2 promotes fibrosis in atrial fibrillation

Fibrosis and inflammation promote atrial fibrillation (AF) and worsen its clinical outcome. The underlying molecular mechanisms, that are relevant for effective antifibrotic drug development, are still under debate. This study deciphers a novel mechanistic interplay between polo-like kinase 2 (PLK2) and the pro-inflammatory cytokine osteopontin (OPN) in the pathogenesis of atrial fibrosis. Compared to sinus rhythm (SR) controls, right atrial appendages and isolated right atrial fibroblasts from AF patients showed downregulation of PLK2 mRNA and protein levels, which were accompanied by remarkable hypoxia-sensitive DNA-methylation of the PLK2 promotor. In an experimental setting, both, genetic deletion and pharmacological inhibition of PLK2 induced myofibroblast differentiation and reduced fibroblast proliferation. Notably, proteomics from PLK2-deleted fibroblasts revealed de novo secretion of OPN. Accordingly, we observed higher OPN plasma levels in AF patients with atrial fibrosis compared to non-fibrosis AF patients. Hence, we provide evidence for PLK2 reactivation and/or OPN inhibition as potential novel targets to prevent fibrosis progression in AF.

pharmacology and toxicology↗

bioRxiv2018

YAP activity is necessary and sufficient for basal progenitor abundance and proliferation in the developing neocortex

The expansion of the neocortex during mammalian evolution has been linked to an enlargement of the subventricular zone during cortical development and an increase in the proliferation of the basal progenitors residing therein. Here, we explored a potential role of YAP, the major downstream effector of the Hippo signaling pathway, in proliferation of basal progenitors. We show that YAP expression and activity are high in ferret and human basal progenitors, which are known to exhibit high proliferative capacity, but low in mouse basal progenitors, which lack such capacity. To induce YAP activity in mouse basal progenitors, we expressed a constitutively active YAP (CA-YAP). This resulted in an increase in proliferation of basal progenitor. In addition, CA-YAP expressing mouse basal progenitors promoted the production of upper-layer neurons. To investigate if YAP is required for the proliferation of basal progenitors, we pharmacologically interfered with the function of YAP in the developing ferret and human neocortex. This resulted in a decrease of cycling basal progenitors. In concert, genetical interference with the function of YAP in ferret developing neocortex resulted in decreased abundance of basal progenitors. Together, our data indicate that YAP promotes the proliferation of basal progenitors and suggest that changes in YAP activity levels contributed to the evolutionary expansion of the neocortex.

neuroscience↗

bioRxiv2017

Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex

To understand the molecular basis underlying the expansion of the neocortex during primate, and notably human, evolution, it is essential to identify the genes that are particularly active in the neural stem and progenitor cells of developing neocortex. Here, we have used existing transcriptome datasets to carry out a comprehensive screen for protein-coding genes preferentially expressed in progenitors of fetal human neocortex. In addition to the previously studied gene ARHGAP11B, we show that ten known and two newly identified human-specific genes exhibit such expression, however with distinct neural progenitor cell-type specificity compared to their ancestral paralogs. Furthermore, we identify 41 additional human genes with progenitor-enriched expression which have orthologs only in primates. Our study not only provides a resource of genes that are candidates to exert specific, and novel, roles in neocortical development, but also reveals that distinct mechanisms gave rise to these genes during primate, and notably human, evolution.

developmental biology↗