Biology subjects

Wigger, L.

Publications and source records attributed to Wigger, L..

5 recordsLinked to original sources

bioRxiv2022

Cortical miR-709 links glutamatergic signaling to NREM sleep EEG slow waves in an activity-dependent manner

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD), altered; while rapid-eye-movement sleep (REMS) rebound was compromised in both, EEG delta (1-4 Hz) power during non-REM sleep (NREMS) was reduced in cKO mice and increased in icKO mice. We subsequently investigated the effects of SD on the miRNA transcriptome and found that the expression of 48 forebrain miRNAs was affected, in particular, the activity-dependent miRNA miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75-1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates endosomal trafficking and glutamatergic receptor activity. A subset of the genes involved in glutamatergic transmission was affected also in the cortices of sleep-deprived, miR-709-inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal excitability during wakefulness to brain synchrony during sleep, likely through the regulation of endosomal trafficking and glutamatergic signaling. Significance StatementMicroRNAs (miRNAs) are key regulators of gene expression playing vital roles both in postnatal brain development and its functioning in adult organisms. Here, we highlight a fundamental role for miRNAs in shaping EEG slow waves, which reflect synchronous neuronal firing, characteristic of NREM sleep (NREMS) in the adult murine cortex. Disruption of the miRNA-biogenesis machinery affected brain synchrony differently, depending on when it occurred during development. Moreover, sleep deprivation altered the expression of several miRNAs in a brain-region specific manner. Among those, we identified miR-709 to affect the expression of genes involved in endosomal-trafficking and glutamatergic-transmission, thereby linking neuronal activity during wakefulness to slow EEG waves during subsequent sleep. The current study causally implicates this specific miRNA and the molecular pathways it targets in modifying the generation of NREMS EEG slow waves, which are important in synaptic plasticity and brain functioning.

neuroscience↗

bioRxiv2021

Reduced light access promotes hypocotyl growth via autophagy-mediated recycling

Plant growth ultimately depends on fixed carbon, thus the available light for photosynthesis. Due to canopy light absorption properties, vegetative shade combines reduced light and a low red to far-red ratio (LRFR). In shade-avoiding plants, these two conditions independently promote growth adaptations to enhance light access. However, how these conditions, differing in photosynthetically-available light, similarly promote growth remains unknown. Here, we show that Arabidopsis seedlings adjust metabolism according to light conditions to supply resources for hypocotyl growth enhancement. Transcriptome analyses indicate that reduced light induces starvation responses, suggesting a switch to a catabolic state to promote growth. Accordingly, reduced light promotes autophagy. In contrast, LRFR promotes anabolism including biosynthesis of plasma-membrane sterols downstream of PHYTOCHROME-INTERACTING FACTORs (PIFs) acting in hypocotyls. Furthermore, sterol biosynthesis and autophagy are indispensable for shade-induced hypocotyl growth. We conclude that vegetative shade enhances hypocotyl growth by combining autophagy-mediated recycling and promotion of specific anabolic processes. HIGHLIGHTSO_LIReduced light and LRFR induce catabolism and anabolism, respectively C_LIO_LIReduced light promotes autophagy to enhance hypocotyl growth in vegetative shade C_LIO_LILRFR enhances hypocotyl growth by promoting plasma membrane lipid biosynthesis C_LIO_LIIn LRFR, PIFs promote sterol biosynthesis specifically in the hypocotyl C_LI

plant biology↗

bioRxiv2020

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories toward type 2 diabetes

Existing studies do not sufficiently describe the molecular changes of pancreatic islet beta cells leading to their deficient insulin secretion in type 2 diabetes (T2D). Here we address this deficiency with a comprehensive multi-omics analysis of metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum from normoglycemia to T2D. Islet pools isolated from surgical samples by laser-capture microdissection had remarkably heterogeneous transcriptomic and proteomic profiles in diabetics, but not in non-diabetic controls. Transcriptomics analysis of this unique cohort revealed islet genes already dysregulated in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive but disharmonic remodeling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or trans-differentiation stages in T2D. Further, integration of islet transcriptomics and pre-operative blood plasma lipidomics data enabled us to define the relative importance of gene co-expression modules and lipids positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.

bioinformatics↗

bioRxiv2019

System analysis of the functional cross-talk between PPAR , LXR and FXR in the human HepaRG liver cells

Transcriptional regulations exert a critical control of metabolic homeostasis. In particular, the nuclear receptors (NRs) are involved in regulating numerous pathways of the intermediate metabolism. The purpose of the present study was to explore in liver cells the interconnectedness between three of them, LXR, FXR, and PPAR, all three known to act on lipid and glucose metabolism, and also on inflammation. The human cell line HepaRG was selected for its best proximity to human primary hepatocytes. Global gene expression of differentiated HepaRG cells was assessed after 4 hours and 24 hours of exposure to GW3965 (LXR agonist), GW7647 (PPAR agonist), and GW4064 and CDCA (FXR synthetic and natural agonist, respectively). Our work revealed that, contrary to our expectations, NR specificity is largely present at the level of target genes, with a smaller than expected overlap of the set of genes targeted by the different NRs. It also highlighted the much broader activity of the synthetic FXR ligand compared to CDCA. More importantly, our results revealed that activation of FXR has a pro-proliferative effect and decreases polyploidy of hepatocytes, while LXR inhibits the cell cycle progression, inducing hepatocyte differentiation and a higher polyploidism. Conclusion: these results highlight the importance of analyzing the different NR activities in a context allowing a direct confrontation of each receptor outcome, and reveals the opposite role of FXR and LXR in hepatocyte cells division and maturation.

physiology↗

bioRxiv2018

Sensory neuron lineage mapping and manipulation in the Drosophila olfactory system

Nervous systems exhibit myriad cell types, but understanding how this diversity arises is hampered by the difficulty to visualize and genetically-interrogate specific lineages, especially at early developmental stages prior to expression of unique molecular markers. Here, we use a genetic immortalization method to analyze the development of sensory neuron lineages in the Drosophila olfactory system, from their origin to terminal differentiation. We apply this approach to first define a fate map of all olfactory lineages and refine the model of temporal patterns of lineage divisions. Taking advantage of a selective marker for the lineage that gives rise to Or67d pheromone-sensing neurons and a genome-wide transcription factor RNAi screen, we identify the spatial and temporal requirements for Pointed, an ETS family member, in this developmental pathway. Transcriptomic analysis of wild-type and Pointed-depleted olfactory tissue reveals a universal requirement for this factor as a switch-like determinant of fates in these sensory lineages.

neuroscience↗