Biology subjects

Srivastava, M.

Publications and source records attributed to Srivastava, M..

At least 19 recordsLinked to original sources

bioRxiv2026

An expanded evolutionary landscape of H3 histones with variants that destabilize nucleosomes and promote chromatin accessibility

Histones are among the most conserved proteins in eukaryotes, yet many animal lineages have evolved divergent histone variants with specialized functions. Some broadly conserved variants (e.g., H3.3) have been linked to the regulation of chromatin accessibility in stem cells, but whether highly divergent variants function similarly remains unclear. Here, we characterize the histone repertoire of the acoel Hofstenia miamia, an animal that can undergo whole-body regeneration using adult pluripotent stem cells (aPSCs). We identify two novel histone H3 paralogs, H3-a and H3-b, that are expressed in aPSCs and form a lineage-specific sister clade to H3.2 and H3.3. Despite substantial sequence divergence and reduced compatibility with canonical chaperone machinery, both variants assemble bona fide nucleosomes in vitro. These nucleosomes exhibit reduced stability and incomplete DNA wrapping, and a cryo-EM structure of the H3-b nucleosome reveals the disruption of conserved histone-DNA contacts. In vivo, H3-a and H3-b are upregulated following injury, and their depletion reduces genome-wide chromatin accessibility, suggesting a role in the maintenance of accessible chromatin during regeneration. A survey of H3 sequences across animal phyla shows that H3-a and H3-b belong to a broader landscape of highly divergent H3 proteins, some of which exhibit sequence differences across both the N-terminal tail and histone-fold domain. Together, these findings link histone sequence diversification to chromatin regulation in aPSCs and highlight the underappreciated evolutionary diversity and functional potential of divergent animal H3 proteins.

evolutionary biology↗

bioRxiv2026

Cell-lineage selection interacts with development and life history to shape the rates and identity of heritable mutations

Mutation rates determine the supply of heritable variation and are central to evolutionary theory, yet they are usually treated as properties of molecular mutational processes. We hypothesised that mutation rates are also shaped by selection among cell lineages within organisms and that the strength of this process depends on developmental and life-history traits. To test the extent of this idea, we combined mathematical modelling with experiments in Drosophila melanogaster and treated mutation rates as emergent properties of interactions among molecular mutagenesis, development, life history, and cell-lineage selection. The model predicts that even modest effects of mutations on cellular fitness can substantially alter the probability that mutations are transmitted, and that these effects depend strongly on developmental architecture, germline dynamics, and time to reproduction. In Drosophila, we experimentally demonstrate biased transmission of a mutation affecting cellular proliferation and show that this bias changes over the reproductive lifespan of the individual. Extending the model genome-wide reveals that the cellular distribution of fitness effects and its interaction with developmental parameters influence both the estimated mutation rate and the composition of transmitted mutations, producing transmission biases that favour mutations with particular cellular fitness effects. These results suggest that developmental and life-history parameters determine how cellular fitness effects translate into transmission bias; therefore, estimates of heritable mutational input can vary from species to species even under constant molecular mutagenesis. By filtering mutations before they enter populations, developmental and life-history evolution can modify both the rate and the nature of heritable variation and thereby influence evolutionary trajectories.

evolutionary biology↗

bioRxiv2026

Molecular MRI of Neuroinflammation in Alzheimer's Disease using a Folate-targeted Nanoprobe

Background: Neuroinflammation, driven by activated microglia, plays a central role in the pathogenesis of Alzheimer's disease (AD). Non-invasive imaging of neuroinflammation holds promise for advancing our understanding of disease mechanisms and evaluating anti-inflammatory therapeutic strategies. The folate receptor (FR), specifically its {beta} isoform, has been identified as a marker of pro-inflammatory myeloid cells in peripheral inflammatory diseases; however, its association with AD neuroinflammation remains unknown. In this work, we first determined FR expression in microglia in mouse models of AD and subsequently evaluated molecular MRI (mMRI) using a folate-targeted nanoprobe for in vivo imaging of the folate receptor expression. Methods and results: Microglial activation and FR expression in APP/PS1 and P301S transgenic mouse models of AD was measured using flow cytometry. A FR-targeted nanoprobe for mMRI was prepared by functionalizing high T1-relaxivity liposomal gadolinium nanoparticle with folic acid. Following intravenous injection, localization of the nanoprobe in the brains of aged transgenic and wild-type mice was measured using T1-weighted MRI. Post-mortem microscopy measured nanoprobe localization relative to microglia and amyloid pathology. In both mouse models, FR{beta} was significantly (p < 0.05) upregulated in pro-inflammatory microglia expressing TNF and IL-1{beta}. The folate-targeted nanoprobe demonstrated MR signal enhancement in the cortical and hippocampal regions of transgenic mice but not in wild type mice; non-targeted nanoprobe control did not demonstrate signal enhancement in brain of transgenic mice. Microscopy confirmed colocalization of FR-targeted nanoprobe with IBA1-positive microglia/macrophages and amyloid plaques. Conclusions: Pro-inflammatory microglia exhibit elevated levels of FR, and its measurement by non-invasive mMRI is a promising marker of neuroinflammation in AD.

neuroscience↗

bioRxiv2026

KDM6A Loss Confers an Invasive Phenotype in Osteosarcoma by Activating Cytoplasmic YAP-Dependent β-catenin Stabilisation

Osteosarcoma (OS) is the most common primary malignant bone tumour and is characterised by aggressive growth, early metastasis, and a very stagnant clinical outcome. Although epigenetic dysregulation has been implicated in OS progression, the mechanisms linking epigenetic alterations to metastatic signalling remain unclear. Here, we identified the lysine-protein demethylase 6A (KDM6A/UTX) as a critical suppressor of OS metastasis and uncovered a novel regulatory axis involving the Hippo/YAP and Wnt/{beta}-catenin signalling. Initial bioinformatics analyses revealed frequent KDM6A alterations and significantly reduced expression in OS patient datasets, which correlated with metastatic disease and poor prognosis. Functional inhibition of KDM6A by pharmacological inhibitors and siRNA induced a hyper-invasive phenotype, marked by elevated mesenchymal markers, enhanced cytoskeletal remodelling, increased transendothelial adhesion and decreased chemotherapeutic drug sensitivity. Importantly, restoration of KDM6A expression effectively counteracted these effects. Mechanistically, KDM6A loss activated Wnt/{beta}-catenin signalling, resulting in nuclear translocation of {beta}-catenin and transcriptional activation of genes associated with stemness and invasion. Therefore, inhibition of {beta}-catenin reversed the invasive phenotype. Further analysis revealed that KDM6A regulated Hippo signalling through epigenetic control of the negative regulator of Yes-Associated Protein (YAP)-LATS1. KDM6A inhibition led to enrichment of H3K27me3, a repressive mark, at the LATS1 promoter. Accumulated YAP was predominantly localised in the cytoplasm, where it interacted with GSK3{beta} and contributed to the stabilisation of {beta}-catenin by preventing its proteasomal degradation. Collectively, our findings identify a novel KDM6A-LATS1-YAP-{beta}-catenin signalling axis that drives metastatic progression in OS.

cancer biology↗

bioRxiv2025

Cholesterol-mediated activation of VapC12 toxin modulates growth and drug susceptibility in Mycobacterium tuberculosis

Tuberculosis eradication efforts are severely hampered by antimicrobial resistance (AMR). We have previously reported that VapBC12 TA system in Mycobacterium tuberculosis (M. tuberculosis) regulates both disease and antibiotic persistence in tuberculosis. In this study, we developed a mechanistic understanding of the VapBC12-dependent modulation of growth and antibiotic susceptibility in M. tuberculosis. We identified a unique Cholesterol Recognition Amino acid Consensus (CRAC) motif in VapC12 toxin and demonstrated that its heterologous expression induces toxicity in M. smegmatis. We have solved the crystal structure of VapB12 antitoxin at a 1.6A0 wavelength and using molecular modeling predicted the structure of TA complex. Structure-function analysis revealed specific residues critical for the assembly and activity of the VapBC12 TA system. Our study suggests that cholesterol activates the VapC12 toxin by competitively displacing its cognate antitoxin at the CRAC motif which consequently restricts the growth of M. tuberculosis. Finally, we demonstrated that chemical inhibition of VapC12 prevents growth restriction and potentiates activity of anti-TB drugs.

microbiology↗

bioRxiv2025

Distributed neural computation and the evolution of the first brains

The origin of brains in the Precambrian was a landmark in animal evolution, enabling new behavior and life histories. Brains likely evolved from diffuse nerve nets, but we do not know what the first brains looked like or how they were organized. Acoel worms, the likely sister lineage to all other animals with brains, offer a unique window into this transition. Here, we studied the acoel worm Hofstenia miamia, a marine predator that hunts planktonic invertebrates and displays other sophisticated behavior. We found that H. miamia has an unusual diffuse brain: a subepidermal network of dense neuropil exhibiting little regionalization or stereotypy in gross anatomy or distribution of neural cell types. Remarkably, we found that behavior in H. miamia is robust to large, arbitrary amputations of brain regions, suggesting that most regions can perform most computations. More brain tissue improves performance, especially on challenging tasks, but no specific brain region is required. These results lead us to propose that H. miamias brain is composed of computationally pluripotent "tiles" that interact to generate coherent behavior. This architecture suggests a trajectory for nervous system evolution in which early brains may have arisen through the condensation of diffuse nerve nets into unregionalized brains, with regionalization evolving secondarily.

neuroscience↗

bioRxiv2025

Interferon gamma signaling drives cardiac metabolic rewiring

BackgroundIFN-gamma (IFN-{gamma}) signaling influences myocardial inflammation and fibrosis across a wide range of conditions, including ischemic and non-ischemic heart failure (HF). However, the direct effects of IFN-{gamma} on cardiomyocytes remain poorly understood. Here, we developed a novel in vivo model to investigate how IFN-{gamma} impacts myocardial metabolism and function. MethodsMale C57BL/6J mice were injected intravenously with hepatotropic adeno-associated virus (AAV2/8) carrying Ifng and nLuc reporter under the albumin promoter (AAV- Ifng) or empty vector control virus (AAV-ctrl). Cardiac alterations were monitored on day 28 through flow cytometry, bulk RNA sequencing, targeted metabolomics, isolated mitochondrial activity, echocardiography, and in vivo imaging using [18F]fluordeoxyglucose ([18F]FDG) and [18F]fluoro-6-thia-heptadecanoic acid. Additionally, mice lacking IFN-{gamma} receptor expression in cardiomyocytes (Myh6Cre Ifngr1fl/fl) were used to further dissect the cell-intrinsic roles of IFN-{gamma} signaling in cardiomyocyte metabolic reprograming. ResultsAfter confirming liver-specific viral transfection and elevated serum IFN-{gamma} production at physiological levels, we observed cardiac metabolic adaptation and rewiring in animals treated with AAV-Ifng compared to control animals. Myocardial bulk RNA sequencing and gene set enrichment analysis identified an IFN-{gamma} response signature accompanied by marked down-regulations of oxidative phosphorylation and fatty acid oxidation pathways. Functional assessment of isolated cardiac mitochondria showed decreased oxygen consumption, and targeted metabolomics confirmed metabolic shifts toward glycolysis in mice overexpressing IFN-{gamma}. In vivo imaging confirmed increased cardiac glucose uptake following AAV-Ifng treatment. Notably, these metabolic alterations were abrogated in mice with cardiomyocyte-specific deletion of IFN-{gamma} receptors (IFNGR). ConclusionsSystemic IFN-{gamma} induces pronounced metabolic reprogramming in the heart, characterized by increased glucose uptake and reduced oxidative phosphorylation, via direct signaling through cardiomyocyte IFNGR. These alterations mirror those observed in aging and some forms of HF, thereby highlighting that, beyond classical inflammation, this cytokine regulates cardiac metabolism. Novelty and significanceO_ST_ABSWhat is known?C_ST_ABSO_LIImmunological mechanisms can impact myocardial disease progression through complex context-dependent mechanisms. C_LIO_LIIFN-{gamma}, a cytokine primarily secreted by natural killer and T cells, promotes myocardial inflammation and fibrosis in the context of autoimmune myocarditis, pressure-overload-induced heart failure, and Chagas cardiomyopathy. C_LIO_LICytokines exert pleiotropic effects and can influence inflammatory responses through mechanisms involving control of energy metabolism. C_LI What new information does this article contribute?O_LIA novel adeno-associated virus model of systemic IFN-{gamma} elevation allows assessment of cardio-immune-metabolic crosstalk without confounding factors. C_LIO_LIIFN-{gamma} drives cardiac metabolic reprogramming in inflammatory contexts, characterized by enhanced glucose uptake and glycolysis with mitochondrial dysfunction, ultimately altering cardiac metabolic fluxes and function. C_LIO_LIThe IFN-{gamma}-induced cardiac metabolic reprogramming is, at least in part, mediated through direct signaling via receptors on cardiomyocytes. C_LI

immunology↗

bioRxiv2025

Development of an EPR-based methodology to study protein-lipid interaction

The interaction of protein with other biomolecules is central to all cellular processes. In particular, protein-lipid interactions play an essential role in regulating soluble and membrane protein function, structure, and dynamics. However, probing these interactions remains challenging due to the complexity and heterogeneity of membranes. Various methods have been developed to characterize protein-membrane interaction, each presenting advantages and limitations. This study presents a robust methodology based on continuous-wave Electron Paramagnetic Resonance (CW-EPR) spectroscopy to characterize protein-membrane interactions. We focused on the protein Tau, an intrinsically disordered protein associated with neurodegenerative diseases. We show that the interaction of labelled Tau with lipids gives rise to a very distinct lineshape, which can be used to quantify the fraction of bound protein. This allows to obtain the apparent binding mode and affinity through titration experiments. In addition, we show that a single measurement provides the absolute concentration of free and bound protein. We argue that this information, which is rarely obtained by other methods providing relative signals, is very useful for mechanistic studies. Furthermore, using mathematical modeling, we developed a minimal-data approach and demonstrated that a single EPR measurement can be used to derive binding constants. The approach is applied to the Taumembrane interaction occurring in different conditions affecting the binding behavior. The presented methodology is expected to be applicable to other proteins. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/672991v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@19cf0c5org.highwire.dtl.DTLVardef@833209org.highwire.dtl.DTLVardef@149fd8corg.highwire.dtl.DTLVardef@a4f50a_HPS_FORMAT_FIGEXP M_FIG C_FIG TOC Figure. Schematic representation of EPR-based analysis of Tau-membrane interactions using spin-labeled Tau and POPS vesicles

biophysics↗

bioRxiv2025

Predicting the topography of fitness landscapes from the structure of genotype-phenotype maps

Ruggedness, the prevalence of fitness peaks, and navigability, the existence of fitness-increasing paths to a target, are key factors affecting evolution on fitness landscapes. We analytically predict landscape ruggedness for genotype-phenotype maps with randomly assigned fitness, using only the sizes of neutral components - mutationally connected genotype sets sharing the same phenotype- and their evolvabilities, the number of neighbouring phenotypes. Further, more evolvable peaks tend to have higher fitness and a minimal evolvability is required for navigability.

evolutionary biology↗

bioRxiv2025

Totipotency and high plasticity in an embryo with a stereotyped, invariant cleavage program

Animal embryos begin as totipotent zygotes, which undergo cell divisions and produce progeny with restricted fate potentials over time. However, the timing of when totipotency is lost and the processes through which embryonic cells acquire fates vary across species. Embryos with invariant cleavage programs, e.g. of nematodes and spiralians, tend to show early restriction of blastomere potency and limited robustness to perturbation, particularly after asymmetric cleavages have occurred. In contrast, embryos with variant cleavage programs, e.g. of vertebrates, tend to specify fates later in development and correspondingly show higher plasticity at early stages. Here, we investigate the embryos of the acoel Hofstenia miamia, which represents an understudied phylum (Xenacoelomorpha) that is distantly related to well-studied developmental systems. Given the invariant duet cleavage program observed in H. miamia embryos, we found unexpected robustness in this species. Isolated 4-cell stage macromeres, the products of an asymmetric, fate specifying cleavage, were totipotent, forming whole organisms upon isolation. Notably, these isolated macromeres produced pharyngeal and neuronal tissues, which they do not produce during normal development. This assay is highly reproducible and can be done at high throughput in H. miamia, making this species an ideal system to investigate the causes of totipotency after specification. Photoconversion-based lineage tracing revealed that rescued cell types are not merely replaced by neoblasts, the adult pluripotent stem cells in H. miamia, suggesting that the macromeres totipotency is the result of changes in the fate potentials of early embryonic cells. Remarkably, all blastomeres at the 8-cell stage were capable of reprogramming their fates in embryo reconstitution assays. By assembling different subsets of 8-cell stage blastomeres, none of which are totipotent on their own, we determined that a minimal unit of two blastomeres, one macromere that produces gut and neoblasts and one micromere that is specified to produce muscle and epidermis, was sufficient to develop into a hatchling worm. Future studies of this system could identify the precise mechanisms that can enable tremendous plasticity, including post-zygotic totipotency, in an embryo with well-defined cellular lineages.

developmental biology↗

bioRxiv2025

Early cell cycle genes in cortical organoid progenitors predict interindividual variability in infant brain growth trajectories

Human induced pluripotent stem cell (iPSC) derived cortical organoids (hCOs) model neurogenesis on an individuals genetic background. The degree to which hCO phenotypes recapitulate the brain growth of the participants from which they were derived is not well established. We generated up to 3 iPSC clones from each of 18 participants in the Infant Brain Imaging Study, who have undergone longitudinal brain imaging during infancy. We identified consistent hCO morphology and cortical cell types across clones from the same participant. hCO cross-sectional area and production of cortical hem cells were associated with in vivo cortical growth rates. Cell cycle associated genes expression in early progenitors at the crux of fate decision trajectories were correlated with cortical growth rate from 6-12 months of age, and were enriched in microcephaly and neurodevelopmental disorder genes. Our data suggest the hCOs capture inter-individual variation in cortical cell types influencing infant cortical surface area expansion.

neuroscience↗

bioRxiv2025

Cooperation between proximate cell layers drives large-scale wound closure prior to whole-body regeneration

Wound closure is an essential aspect of successful regeneration, often acting as the first morphogenetic event that precedes downstream cellular events. Despite heavy investment in studying whole-body regeneration in many invertebrate systems, the steps by which these organisms heal their wounds remain understudied. Here, we investigate the cellular mechanisms of wound healing in the acoel Hofstenia miamia, an invertebrate worm capable of whole-body regeneration. H. miamia have two distinct epithelial layers, an outer epidermis and the epithelial lining of their pharynx. By labeling regenerating fragments with an actin dye, we found that H. miamia use distinct mechanisms of epithelial wound repair across different injury contexts. In transverse wounds that dont injure the pharyngeal epithelium, the epidermis closes by gradual radial constriction. In contrast, injuries that damage both the epidermis and the pharyngeal epithelium show the formation of long, actin-rich protrusions that cross the wound gap and form heterotypic bridges prior to re-epithelialization. Muscle contraction is required for the formation of heterotypic bridges - when animals are anesthetized and immobile, they are unable to form these cellular bridges, and epidermal cells cannot migrate independently. Global actomyosin contractility also plays a role in repair mechanisms, and pharmacological perturbation of contractility shifts the dynamics of wound closure after amputation. In the presence of blebbistatin, heterotypic bridge formation is inhibited but homotypic re-epithelialization is accelerated through increased cell crawling. Together, this work identifies mechanisms by which epithelial layers close large wounds in vivo, identifying novel heterotypic cellular bridges in wound closure and demonstrating the conservation of actin-mediated processes in an early-diverging phylum.

cell biology↗

bioRxiv2025

The evolution of mutation rates in the light of development and cell-lineage selection

Mutation rates drive the pace and potential of evolutionary change. However, to better understand the evolutionary implications of mutation rates, there is a need to uncover the causes of their diversification. In multicellular organisms, all mutations first arise in a single cell in a developmental context. Whether a mutation enters a populations gene pool can therefore depend on developmental events that affect the likelihood of mutant cell lineages of producing gametes. For this reason, the evolution of mutation rates in populations is governed not only by changes in the rates at which mutations occur at the molecular level, but also by changes in developmental features of organisms and how mutations impact cellular fitness during development. We present a theoretical framework that, supported by empirical data from mammals and experiments on the fruit fly, demonstrate how generational mutation rates can be shaped by changes in developmental parameters and intraorganismal selective processes even when molecular mutation rates are presumed constant. Our model highlights how the diversity of mutation rates observed across animals may be the byproduct of organismal development rather than the result of direct selection against mutator alleles. As such, development not only introduces phenotypic biases, it also shapes the rates and trajectories of genetic diversity and is thus at the core of evolutionary theory.

evolutionary biology↗

bioRxiv2025

Sequence-dependent co-condensation of Lsr2 with DNA elucidates the mechanism of genome compaction in Mycobacterium tuberculosis

The xenogeneic silencer protein Lsr2 from Mycobacterium tuberculosis plays a critical role in its survival and pathogenesis. Lsr2 is a nucleoid-associated protein that interacts with DNA in vivo and regulates many genes. Purified Lsr2 forms nucleoprotein filaments with DNA molecules leading to highly compacted DNA conformations. However, the physical mechanism underlying Lsr2-mediated DNA compaction, resulting in gene regulation, remains elusive. We employed a combination of biochemical assay, single-molecule imaging, and molecular dynamics simulations to investigate the governing principles of Lsr2-mediated DNA compaction. We show that, while Lsr2 alone undergoes phase separation, addition of DNA substantially lowers the required concentration for its phase separation. Strikingly, our single-molecule and simulation data establish that Lsr2 forms condensates with long stretches of AT-rich DNA, providing strong evidence for sequence-dependent co-condensation. This observation is contrary to the classical view of sequence-dependent binding of individual protein molecules to DNA, our findings rather suggest that protein-DNA co-condensates sense the average binding energy landscape. We present a physical model for Lsr2-mediated DNA compaction and gene regulation, describing a novel mechanism for NAP-mediated genome organization in bacteria.

biophysics↗

bioRxiv2025

Localized Reconstruction of Multimodal Distance Distribution from DEER Data of Biopolymers

Pulsed Dipolar ESR Spectroscopy (PDS) is a uniquely powerful technique to characterize the structural property of intrinsically disordered proteins (IDPs) and polymers and the conformational evolution of IDPs and polymers, e.g. during assembly, by offering the probability distribution of segment end-to-end distances. However, it is challenging to determine distance distribution P(r) of IDPs by PDS because of the uncertain and broad shape information that is intrinsic to the distance distribution of IDPs. We demonstrate here that the Srivastava-Freed Singular Value Decomposition (SF-SVD) point-wise mathematical inversion method along with wavelet denoising (WavPDS) can aid in obtaining reliable shapes for the distance distribution, P(r), for IDPs. We show that broad regions of P(r) as well as mixed narrow and broad features within the captured distance distribution range can be effectively resolved and differentiated without a priori knowledge. The advantage of SF-SVD and WavPDS is that the methods are transparent, requiring no adjustable parameters, the processing of the magnitude for the probability distribution is performed separately for each distance increment, and the outcome of the analysis is independent of the users judgement. We demonstrate the performance and present the application of WavPDS and SF-SVD on model ruler molecules, model polyethylene glycol polymers with end-to-end spin labeling, and IDPs with pairwise labeling spanning different segments of the protein tau to generate the transparent solutions to the P(r)s including their uncertainties and error analysis.

biophysics↗

bioRxiv2024

High-speed 10-plex DNA-PAINT with a larger sequence repertoire

DNA-Points Accumulation for Imaging in Nanoscale Topography (DNA-PAINT) enables multiplexed super-resolution imaging of biological samples. We expand the repertoire of speed-optimized DNA sequences for DNA-PAINT imaging to drive visualization of as many as twelve targets in a sequential manner with molecular resolution. By implementing Exchange-PAINT protocol, we demonstrate 12-plex super-resolved imaging of docking strand patterned DNA origami nanostructures within four hours with a localization precision of 3 to 5 nm. Using these sequences, we demonstrate 9-plex super-resolution imaging of diverse nuclear targets within four hours. Further, we present a comprehensive analysis pipeline to quantify nanoscale chromatin in single cells. The combination of multiplexed imaging and analysis pipeline enabled us to reveal the loss of chromatin contacts with nuclear speckles upon global transcription inhibition. This work highlights the versatility of our approach to simultaneously image multiple targets at accelerated speeds while maintaining precise spatial localization for each target, enabling in depth mapping of the nuclear landscape. These speed-optimized imager sequences for high multiplexed super-resolution imaging will drive its further adoption for diverse cellular imaging applications.

biophysics↗

bioRxiv2024

A spreading, multi-tissue wound signal initiates whole-body regeneration

ABSTRACTAnimal bodies are equipped to sense injuries and respond, and rapid activation of ERK signaling at wound sites has emerged as a recurring mechanism across metazoans. During whole-body regeneration, distant species including cnidarians, planarians and echinoderms activate ERK at wounds to drive early transcriptional changes. However, it is unclear to what extent these are distinct phenomena, utilizing a common effector pathway but with different upstream inputs and downstream functions, or are more deeply alike, sharing upstream inputs, activating cell type(s), or spatiotemporal dynamics. To facilitate thorough comparisons across animals, we examined wound-induced ERK during whole-body regeneration in the acoel Hofstenia miamia. ERK signaling is induced at wound sites within 10 minutes post-amputation and peaks in activity within one hour. ERK is required for head and tail regeneration and inhibiting ERK suppresses the expression of wound-induced genes, which are themselves required for regeneration. Quantification of spatial dynamics revealed that active ERK spreads rapidly away from the wound site during the first 30 minutes post-amputation and continues to expand in space through 3-6 hours, albeit at lower levels. Multiple cell types activate ERK including neoblasts (stem cells) and muscle, and ERK is spatially dynamic within both cell types, however, ERK activation in muscle does not require neoblasts. Finally, neuregulin-1, a putative ligand produced exclusively by muscle cells, is required for ERK activation at wounds. Altogether, our data identify a key signaling role of muscle cells in driving ERK activation in multiple cell types after injury, and describe a spatial spreading phenomenon with parallels to dynamic ERK patterns in other systems.

developmental biology↗

bioRxiv2024

Accelerated amyloid deposition in SARS-CoV-2 infected mouse models of Alzheimer's disease

Familial Alzheimers disease (AD) involving known AD causing genes accounts for a small fraction of cases, the vast majority are sporadic. Neuroinflammation, secondary to viral infection, has been suggested as an initiating or accelerating factor. In this work we tested the hypothesis that SARS-CoV-2 (SCV2) viral infection accelerates the development of AD pathology in mouse models of AD. We profiled transcriptomic changes using transgenic APP/PSEN1 and P301S mouse models that develop AD pathology and k18hACE2 mice that express the humanized ACE2 receptor used by SCV2 to enter cells. This study identified the interferon and chemokine responses constituting key shared pathways between SCV2 infection and the development of AD pathology. Two transgenic mouse models of AD: APP/PSEN1 (develops amyloid pathology) and 3xTg AD (develops both amyloid and tau pathology) were crossed with k18-hACE2 mice to generate hybrid hACE2-3xTg and hACE2-APP/PSEN1 mice. Neuroinflammation and amyloid deposition in the brain of infected mice were imaged in vivo using molecular MRI (mMRI) probes and confirmed postmortem by histopathology. Results show that 11-14-month-old SCV2 infected hACE2-3xTg mice exhibit neuroinflammation 10 days post infection and 4-5-month-old hACE2-APP/PS1 hybrid mice develop amyloid deposits, while age-matched uninfected mice exhibit neither phenotype. This suggests that SCV2 infection could induce or accelerate AD when risk factors are present.

neuroscience↗