Biology subjects

Winkler, S.

Publications and source records attributed to Winkler, S..

39 records · Page 3Linked to original sources

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↗

bioRxiv2017

Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11

Retinitis pigmentosa is a clinically heterogeneous disease affecting 1.6 million people worldwide. A growing number of identified disease-causing genes are associated with the spliceosome, but the molecular consequences that link defects in splicing factor genes to the aetiology of the disease remain to be elucidated. In this paper, we present a Drosophila model for Retinitis pigmentosa 11, a human disease caused by mutations in the splicing factor PRPF31. Here, we induced mutations in the Drosophila orthologue Prp31. Mutant flies are viable and show a normal eye phenotype when kept under regular light conditions. However, when exposed to constant light, photoreceptors of mutant flies degenerate, thus resembling the human disease phenotype. Degeneration could be shown to be associated with increased oxidative stress. This increase was in agreement with severe dysregulation of genes involved in oxidation/reduction processes, as revealed by high throughput transcriptome sequencing. In fact, light induced photoreceptor cell degeneration could be attenuated by experimentally reducing oxidative stress. A comparable decrease in retinal degeneration was achieved by raising mutant larvae on a vitamin A-depleted medium, thereby reducing rhodopsin levels. Finally, transcriptome data further uncovered an overall retention of introns in mRNAs. Among those, mRNAs of genes involved in synapse assembly, growth and stability were most prominent. These results point to a multifactorial genesis of light induced degeneration in retinae of Prp31 mutant flies, including transcriptional and splicing dysregulation, oxidative stress and defects in vitamin A metabolism.

genetics↗

bioRxiv2017

Loss Of lrrk2 Impairs Cell Proliferation And Neuronal Regeneration In The Zebrafish Brain

LRRK2 mutations are a major cause of Parkinsons disease. Pathogenicity of LRRK2 loss-of-function is controversial, as knockout in rodents reportedly induces no brain-specific effects and knockdown studies in zebrafish are conflicting. Here we show that CRISPR/Cas9-engineered deletion of the ~60-kbp-long zebrafish lrrk2 locus elicits a pleomorphic, albeit transient brain phenotype in maternal-zygotic mutants (mzLrrk2). Intriguingly, 11-month-old mzLrrk2 adults display increased dopamine and serotonin catabolism. Additionally, we find decreased mitosis in the larval brain and reduced stab injury-induced neuronal regeneration in the adult telencephalon. Finally, hypokinesia associates with loss of lrrk2 in larvae. Our results demonstrate that lrrk2 knockout has an early neurodevelopmental effect, and leads to perturbed dopamine and serotonin catabolism in a LRRK2 knockout. We propose mzLrrk2 zebrafish as a valuable tool to study LRRK2 loss-of-function in vivo, and provide a link between LRRK2 and the control of basal cell proliferation in the brain that may become potentially critical upon challenges like brain injury.

neuroscience↗