Biology subjects

Mann, O.

Publications and source records attributed to Mann, O..

3 recordsLinked to original sources

bioRxiv2024

Spatial targeting of the prostaglandin receptor EP2 to very early endosomes co-ordinates PGE2-mediated cAMP signaling in decidualizing human endometrium

Decidualization denotes the differentiation of endometrial stromal cells into specialized decidual cells, essential for embryo implantation and pregnancy. The process requires coordinated activation of both progesterone and cAMP signaling pathways, which converge on downstream transcription factors. PGE2 and relaxin, acting respectively through their Gs-coupled GPCRs EP2 and RXFP1, are putative candidates responsible for generating cAMP in differentiating stromal cells. Here, we show that PGE2 is less efficacious than relaxin in elevating intracellular cAMP levels in primary stromal cells but more effective at driving the expression of canonical decidual genes. Both PGE2- and relaxin-induced cAMP generation involves receptor internalization, but EP2 is endocytosed into very early endosomes (VEEs). Perturbation of the VEE machinery dysregulates PGE2-dependent cAMP profiles and disrupts key decidual signaling pathways, resulting in a disordered differentiation response. We demonstrate that the spatial location of EP2 is essential for coordinated activation of the downstream signaling cascades that govern decidualization.

cell biology↗

bioRxiv2023

Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity

BackgroundThe development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes is still missing. MethodsLiver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice. ResultsHere we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5p was the most associated to whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5p overexpression. Weight loss in obese mice decreased hepatic miR-182-5p and restored Lrp6 expression and other miR-182-5p target genes. Hepatic overexpression of miR-182-5p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days. ConclusionBy mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/560594v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@e19015org.highwire.dtl.DTLVardef@ba6497org.highwire.dtl.DTLVardef@121f8f4org.highwire.dtl.DTLVardef@15f7773_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2017

A complex performance landscape for suction-feeding reveals constraints and adaptations in a population of reef damselfish

The ability to predict how multiple traits interact in determining performance is key to understanding the evolution of complex functional systems. Similar to Simpsons adaptive landscape, which describes the fitness consequences of varying morphological traits, performance landscapes depict the performance consequences of varying morphological traits. Mapping the populations location with respect to the topographic features of the landscape could inform us on the selective forces operating on the traits that underlie performance. Here, we used a mechanistic model derived from first principles of hydrodynamics to construct a hypothetical performance landscape for zooplankton prey capture using suction feeding. We then used the landscape to test whether a population of Chromis viridis, a coral reef zooplanktivore, is located on a performance peak or ridge based on measurements of kinematic variables recorded in-situ during undisturbed foraging. Observed trait combinations in the wild population closely matched regions of high feeding performance in the landscape, however the population was not located on a local performance peak. This sub-optimal performance was not due to constraints stemming from the observed trait correlations. The predominant directions of variation of the phenotypic traits was tangent to the path of steepest ascent that points towards the local peak, indicating that the population does not reside on a \"performance ridge\". Rather, our analysis suggests that feeding performance is constrained by stabilizing selection, possibly reflecting a balance between selection on feeding performance and mechanical or genetic constraints.

evolutionary biology↗