Biology subjects

Scott, C. A.

Publications and source records attributed to Scott, C. A..

6 recordsLinked to original sources

bioRxiv2024

Mitochondrial dynamics regulate cell size in the developing cochlea

In multicellular tissues, cell size and shape are intricately linked with physiological function. In the vertebrate auditory organ, the neurosensory epithelium develops as a mosaic of sensory hair cells (HCs), and their glial-like supporting cells (SCs), which have distinct morphologies at different frequency positions along its tonotopic long axis. In the chick cochlea, the basilar papilla (BP), proximal (high-frequency) HCs are larger than their distal (low-frequency) counterparts, a morphological feature essential for frequency tuning. Mitochondrial dynamics, which constitute the equilibrium between fusion and fission, regulate differentiation and functional refinement across a variety of cell types. We investigate this a potential mechanism for cell size regulation in developing HCs. Using live imaging in intact BP explants, we identify distinct remodelling of mitochondrial networks in proximal compared to distal HCs. Manipulating mitochondrial dynamics in developing HCs alters their normal morphology along the proximal-distal (tonotopic) axis. Inhibition of the mitochondrial fusion machinery decreased proximal HC size, whilst promotion of fusion increased the distal HC size. We identify mitochondrial dynamics as a key regulator of HC size and morphology in developing inner ear epithelia. Summary StatementMitochondrial remodelling drives developmental changes in cell size in the auditory sensory epithelium. Our data reveal a fundamental mechanism regulating cell size and frequency-place coding in the developing cochlea.

developmental biology↗

bioRxiv2023

Plasticity of gene expression in the nervous system by exposure to environmental odorants that inhibit HDACs

Eukaryotes are often exposed to microbes and respond to their secreted metabolites, such as the microbiome in animals or commensal bacteria in roots. Little is known about the effects of long-term exposure to volatile chemicals emitted by microbes, or other volatiles that we are exposed to over a long duration. Using the model system Drosophila melanogaster, we evaluate a yeast emitted volatile, diacetyl, found in high levels around fermenting fruits where they spend long periods of time. We find that exposure to just the headspace containing the volatile molecules can alter gene expression in the antenna. Experiments showed that diacetyl and structurally related volatile compounds inhibited human histone-deacetylases (HDACs), increased histone-H3K9 acetylation in human cells, and caused wide changes in gene expression in both Drosophila and mice. Diacetyl crosses the blood-brain barrier and exposure causes modulation of gene expression in the brain, therefore has potential as a therapeutic. Using two separate disease models known to be responsive to HDAC-inhibitors, we evaluated physiological effects of volatile exposure. First, we find that the HDAC inhibitor also halts proliferation of a neuroblastoma cell line in culture as predicted. Next, exposure to vapors slows progression of neurodegeneration in a Drosophila model for Huntingtons disease. These changes strongly suggest that unbeknown to us, certain volatiles in the surroundings can have profound effects on histone acetylation, gene expression and physiology in animals.

neuroscience↗

bioRxiv2022

Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control

Genetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example by affecting DNA methylation at CpG dinucleotides (methylation quantitative trait loci - mQTL). Here, we present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation (correlated regions of systemic interindividual variation - CoRSIVs). We used target-capture bisulfite sequencing to assess DNA methylation at 4,086 CoRSIVs in multiple tissues from 188 donors in the NIH Genotype-Tissue Expression (GTEx) program (807 samples total). At CoRSIVs, as expected, DNA methylation in peripheral blood correlates with methylation and gene expression in internal organs. We also discovered unprecedented mQTL at these regions. Genetic influences on CoRSIV methylation are extremely strong (median R2=0.76), cumulatively comprising over 70-fold more human mQTL than detected in the most powerful previous study. Moreover, mQTL beta coefficients at CoRSIVs are highly skewed (i.e., the major allele predicts higher methylation). Both surprising findings were independently validated in a cohort of 47 non-GTEx individuals. Genomic regions flanking CoRSIVs show long-range enrichments for LINE-1 and LTR transposable elements; the skewed beta coefficients may therefore reflect evolutionary selection of genetic variants that promote their methylation and silencing. Analyses of GWAS summary statistics show that mQTL polymorphisms at CoRSIVs are associated with metabolic and other classes of disease. A focus on systemic interindividual epigenetic variants, clearly enhanced in mQTL content, should likewise benefit studies attempting to link human epigenetic variation to risk of disease. Our CoRSIV-capture reagents are commercially available from Agilent Technologies, Inc. Significance StatementPopulation epigeneticists have relied almost exclusively on CpG methylation arrays manufactured by Illumina. At most of the >400,000 CpG sites covered by those arrays, however, methylation does not vary appreciably between individuals. We previously identified genomic loci that exhibit systemic (i.e. not tissue-specific) interindividual variation in DNA methylation (CoRSIVs). These can be assayed in blood DNA and, unlike tissue-specific epigenetic variants, do not reflect interindividual variation in cellular composition. Here, studying just 4,086 CoRSIVs in multiple tissues of 188 individuals, we detect much stronger genetic influences on DNA methylation (mQTL) than ever before reported. Because interindividual epigenetic variation is essential for not only mQTL detection, but also for epigenetic epidemiology, our results indicate a major opportunity to advance this field.

genetics↗

bioRxiv2021

Aerobic glycolysis is important for zebrafish larval wound closure and tail regeneration

The underlying mechanisms of appendage regeneration remain largely unknown and uncovering these mechanisms in capable organisms has far-reaching implications for potential treatments in humans. Recent studies implicate a requirement for metabolic reprogramming reminiscent of the Warburg effect during successful appendage and organ regeneration. As changes are thus predicted to be highly dynamic, methods permitting direct, real-time visualization of metabolites at the tissue and organismal level, would offer a significant advance in defining the influence of metabolism on regeneration and healing. We sought to examine whether glycolytic activity was altered during larval fin regeneration, utilising the genetically encoded biosensor, Laconic, enabling the spatiotemporal assessment of lactate levels in living zebrafish. We present evidence for a rapid increase in lactate levels within minutes following injury, with a role of aerobic glycolysis in actomyosin contraction and wound closure. We also find a second wave of lactate production, associated with overall larval tail regeneration. Chemical inhibition of glycolysis attenuates both contraction of the wound and regrowth of tissue following tail amputation, suggesting aerobic glycolysis is necessary at two distinct stages of regeneration.

developmental biology↗

bioRxiv2021

Matriptase generates a tissue damage response via promoting Gq signalling, leading to RSK and DUOX activation

Tissues respond to damage by increasing inflammation and epithelial cell motility. How damage detection and responses are orchestrated is unclear. Overexpression of the membrane bound protease, Matriptase, or mutation of its inhibitor, Hai1, results in inflamed epithelia, in which cells have increased motility and are prone to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H2O2, Nf{kappa}B signalling, and IP3R-mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit rescues both the hai1a inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated pERK, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as pERK targets disrupting adherens junctions in hai1a mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression.

cell biology↗

bioRxiv2019

Contributions of the conserved insect carbon dioxide receptor subunits to odor detection

The CO2 receptor in mosquitoes is broadly tuned to detect many diverse odorants. The receptor consists of three 7-TM subunits (Gr1, Gr2, and Gr3) in mosquitoes but only two subunits in Drosophila: Gr21a (Gr1 ortholog) and Gr63a (Gr3 ortholog). We demonstrate that Gr21a is required for CO2 responses in Drosophila as has been shown for Gr63a. Next, we generate a Drosophila double mutant for Gr21a and Gr63a, and in this background we functionally express combinations of Aedes Gr1, 2, and 3 genes in the \"CO2 empty neuron.\" Only two subunits, Gr2 and Gr3, suffice for response to CO2. Addition of Gr1 increases sensitivity to CO2 while it decreases the response to pyridine. The inhibitory effect of the antagonist isobutyric acid is observed upon addition of Gr1. Gr1 therefore increases the diversity of ligands of the receptor, and also modulates the response of the receptor complex.

neuroscience↗