Biology subjects

Brakebusch, C.

Publications and source records attributed to Brakebusch, C..

5 recordsLinked to original sources

bioRxiv2023

SC2Spa: a deep learning based approach to map transcriptome to spatial origins at cellular resolution

BackgroundUnderstanding cellular heterogeneity within tissues hinges on knowledge of their spatial context. However, it is still challenging to accurately map cells to their spatial coordinates. ResultsWe present SC2Spa, a deep learning-based approach that learns intricate spatial relationships from spatial transcriptomics (ST) data. Benchmarking tests show that SC2Spa outperformed other predictors and accurately detected tissue architecture from transcriptome. SC2Spa successfully mapped single cell RNA sequencing (scRNA-seq) to Visium assay, providing an approach to enhance the resolution for low resolution ST data. Our test showed that SC2Spa performs well for various ST technologies and robust to spatial resolution. In addition, SC2Spa can suggest spatially variable genes that cannot be identified from previous approaches. ConclusionsSC2Spa is a robust and accurate approach to provide single cells with their spatial location and identify spatially meaningful genes.

bioinformatics↗

bioRxiv2021

Control of cortical cytoskeleton-membrane interaction by RhoA regulates peripheral nerve myelination

Bidirectional transmission of mechanical and biochemical signals is integral to cell-environment communication and underlies the function of Schwann cells, the myelinating glia of the peripheral nervous system. As major integrators of "outside-in" signaling, Rho GTPases link actin cytoskeleton dynamics with cellular architecture to regulate adhesion and cell deformation. Using Schwann cell-specific gene inactivation, we discovered that RhoA promotes the initiation of myelination, axonal wrapping and axial spreading of Schwann cells, and is later required to restrict myelin growth in peripheral nerves. These effects are mediated by modulation of actomyosin contractility, actin dynamics and cortical actin-membrane attachment, which collectively couple tensional forces to intracellular signaling that regulate axon-Schwann cell interaction and myelin synthesis. This work establishes RhoA as an intrinsic regulator of a biomechanical response that controls the switch of Schwann cells towards the myelinating and the homeostatic states.

neuroscience↗

bioRxiv2021

Microglia remodel the synaptic signaling required for context-dependent cognitive performance

Microglial homeostatic functions are fundamental to regulate the central nervous system microenvironment. We use conditional cell-specific gene targeting, RNA-seq profiling, high-throughput proteomics, phosphoproteomics, systems biology, and animal behavior to report a critical role for the RhoGTPase Rac1 in regulating adult microglia physiology. Ablation of Rac1 in adult microglia impaired their ability to sense and interpret the brain microenvironment and affected their capacity to communicate with synapses to drive cognitive performance, both at the steady-state and during experience-dependent plasticity. Overall, our results reveal a novel and central role for Rac1 as a regulator of microglia homeostasis and a molecular driver of the microglia-synapse crosstalk required for context-dependent sociability and learning related to memory.

neuroscience↗

bioRxiv2020

The SPIRE1 actin nucleator coordinates actin/myosin functions in the regulation of mitochondrial motility

Subcellular localisation of mitochondria provides a spatial and temporal organisation for cellular energy demands. Long-range mitochondrial transport is mediated by microtubule tracks and associated dynein and kinesin motor proteins. The actin cytoskeleton has a more versatile role and provides transport, tethering, and anchoring functions. SPIRE actin nucleators organise actin filament networks at vesicle membranes, which serve as tracks for myosin 5 motor protein-driven transport processes. Following alternative splicing, SPIRE1 is targeted to mitochondria. In analogy to vesicular SPIRE functions, we have analysed whether SPIRE1 regulates mitochondrial motility. By tracking mitochondria of living fibroblast cells from SPIRE1 mutant mice and splice-variant specific mitochondrial SPIRE1 knockout mice, we determined that the loss of SPIRE1 function increased mitochondrial motility. The SPIRE1 mutant phenotype was reversed by transient overexpression of mitochondrial SPIRE1, which almost completely inhibited motility. Conserved myosin 5 and formin interaction motifs contributed to this inhibition. Consistently, mitochondrial SPIRE1 targeted myosin 5 motors and formin actin filament generators to mitochondria. Our results indicate that SPIRE1 organises an actin/myosin network at mitochondria, which opposes mitochondrial motility. Summary statementThe mitochondrial SPIRE1 protein targets myosin 5 motor proteins and formin actin-filament nucleators/elongators towards mitochondria and negatively regulates mitochondrial motility.

cell biology↗

bioRxiv2017

Genetic ablation of RhoA in adult microglia causes synapse and neuronal loss

Nervous tissue homeostasis requires regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation producing a neurological phenotype (including synapse and neuron loss, impairment of LTP, formation of {beta}-amyloid plaques and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated Tnf production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also found that the Rhoa/Src signaling pathway was disrupted in microglia of the APP/PS1 mouse model of Alzheimers disease and that low doses of A{beta} oligomers triggered microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing RhoGTPase signaling in microglia can directly cause neurodegeneration.

neuroscience↗