Biology subjects

Meyer, N.

Publications and source records attributed to Meyer, N..

3 recordsLinked to original sources

bioRxiv2020

Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia

Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment option being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI can aid the development of better treatments. Here we have studied the role of lactate receptor HCAR1 (Hydroxycarboxylic acid receptor 1) in tissue repair after HI in mice. We show that HCAR1 knockout (KO) mice have reduced tissue regeneration compared with wildtype (WT) mice. Further, proliferation of neural progenitor cells and microglial activation were impaired after HI. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of WT mice involving about 7300 genes. In contrast, the HCAR1 KO mice showed a very modest response to HI, involving about 750 genes. Notably, fundamental processes involved in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 KO. Taken together, our data suggest that HCAR1 is a key transcriptional regulator of the pathways that promote tissue regeneration after HI. Thus, HCAR1 could be a promising therapeutic target in the treatment of neonatal HI and other forms of brain ischemia.

neuroscience↗

bioRxiv2020

Resolving transcriptional states and predicting lineages in the annelid Capitella teleta using single-cell RNAseq

Evolution and diversification of cell types has contributed to animal evolution. However, gene regulatory mechanisms underlying cell fate acquisition during development remains largely uncharacterized in spiralians. Here we use a whole-organism, single-cell transcriptomic approach to map larval cell types in the annelid Capitella teleta at 24- and 48-hours post gastrulation (stages 4 and 5). We identified eight unique cell clusters (undifferentiated precursors, ectoderm, muscle, ciliary-band, gut, neurons, neurosecretory cells and protonephridia), thus helping to identify previously uncharacterized molecular signatures such as novel neurosecretory cell markers. Analysis of coregulatory programs in individual clusters revealed gene interactions that can be used for comparisons of cell types across taxa. We examined the neural and neurosecretory clusters more deeply and characterized a differentiation trajectory starting from dividing precursors to neurons using Monocle3 and velocyto. Pseudotime analysis along this trajectory identified temporally-distinct cell states undergoing progressive gene expression changes over time. Our data revealed two potentially distinct neural differentiation trajectories including an early trajectory for brain neurosecretory cells. This work provides a valuable resource for future functional investigations to better understanding neurogenesis and the transitions from neural precursors to neurons in an annelid.

developmental biology↗

bioRxiv2020

Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death

Increasing evidence suggests that induction of lethal autophagy carries potential significance for the treatment of glioblastoma (GBM). In continuation of previous work, we demonstrate that pimozide and loperamide trigger an ATG5- and ATG7-dependent type of cell death that is significantly inhibited with the cathepsin inhibitors E64D/Pepstatin A and the lipid ROS scavenger -tocopherol in MZ-54 GBM cells. Global proteomic analysis after treatment with both drugs also revealed an increase of proteins related to lipid and cholesterol metabolic processes. These changes were accompanied by AKT1 (AKT serine/threonine kinase 1) inhibition and a massive accumulation of cholesterol and other lipids in the lysosomal compartment, indicative of impaired lipid transport/degradation. In line with these observations, pimozide and loperamide treatment were associated with a pronounced increase of bioactive sphingolipids including ceramides, glucosylceramides and sphingoid bases measured by targeted lipidomic analysis. Furthermore, pimozide and loperamide inhibited the activity of acid sphingomyelinase (ASM), increased lipid-ROS levels and promoted induction of lysosomal membrane permeabilization (LMP), as well as release of cathepsin B into the cytosol in MZ-54 wt cells. While LMP and cell death were significantly attenuated in ATG5/7 KO cells, both events were enhanced by depletion of the lysophagy receptor VCP (valosin containing protein), supporting a pro-survival function of lysophagy under these conditions. Collectively, our data suggest that pimozide and loperamide-driven autophagy and lipotoxicity synergize to induce LMP and lysosomal cell death. The results also support the notion that simultaneous overactivation of autophagy and induction of LMP represents a promising approach for the treatment of GBM.

cancer biology↗