Biology subjects

Smith, K. A.

Publications and source records attributed to Smith, K. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Conserved Cell Type Signatures Across the Brainstem and Spinal Cord in the Mouse Central Nervous System

Understanding how cell types are organized across the central nervous system (CNS) is key to uncovering neural function. Here, we integrate single-nucleus Multiome (RNA+ATAC) sequencing, spatial transcriptomics, and computational analyses to map conserved cell type signatures in the adult mouse brainstem and spinal cord. We identify a shared core of neuronal and non-neuronal cell types, alongside region-specific specializations reflecting distinct functions. Spatial data reveal conserved cellular niches across the brainstem-spinal cord boundary, indicating a continuous organizational logic. Cross-region comparisons uncover recurrent gene expression modules and signaling programs that may support shared circuit features. Chromatin accessibility profiling highlights cell-type-specific regulatory programs and implicates Hox transcription factors in positional identity. Notably, cell-type and positional identities are largely orthogonal, with varying regional influence across neuronal classes: motor neurons show strong positional coupling, whereas glutamatergic and GABAergic interneurons show minimal entrainment. This work provides a reference for the shared molecular architecture of these CNS regions.

neuroscience↗

bioRxiv2026

A layered standards framework for integrating single-cell and spatial omics data into brain cell atlases

The BRAIN Initiative Cell Atlas Network (BICAN) is generating large-scale multimodal datasets to profile cell types in the human, non-human primate, and mouse brain. The diversity of single-cell and spatial transcriptomic and epigenomic assays, combined with varied experimental contexts, multiple data-generating laboratories and distributed infrastructure, poses substantial challenges for data integration and reuse in BICAN. To address this, we implemented a standards framework that enables layered integration of these data into knowledge-ready products for interoperable brain cell atlases. This framework organizes data based on three progressively structured layers. First, we introduced an assay-agnostic modeling layer that unifies the representation of single-cell and spatial omics data using a common set of biological entities and processes assessed by diverse experimental techniques. Second, we implemented harmonized metadata standards that capture key experimental features linked to biospecimen provenance across heterogeneous tissue sources, species, and preparations, supporting integration and validation while minimizing burden on data contributors. Third, we present an extensible representation for data-driven cell type taxonomies that integrates molecular data with annotations, ontology mappings, and evidence. Together, these contributions represent an end-to-end framework that transforms heterogeneous datasets into structured, interoperable resources that support broad community reuse via mapping algorithms, annotation systems, and visualization platforms. This approach links biospecimen provenance with cell-level outputs and embeds these in a standardized taxonomy format, enabling downstream applications such as cross-dataset integration, reference mapping, and knowledge-driven analysis. More broadly, our work demonstrates a generalizable strategy for enabling an efficient data-to-knowledge pipeline in a large-scale consortium setting.

genomics↗

bioRxiv2026

The External Globus Pallidus is a Basal Ganglia Output Hub with Action-Specific Circuits

The external globus pallidus (GPe) is traditionally viewed as a homogeneous relay in the indirect basal ganglia pathway that broadly suppresses movement. Using whole-brain anterograde axon mapping, rabies tracing, single-neuron reconstruction, and single-nucleus RNA sequencing, we reveal that the GPe is a major basal ganglia output nucleus, composed of anatomically and molecularly distinct populations. Besides the neurons with canonical projections, and projections to striatum and cortex, the GPe contains specific neuronal populations that target the thalamus and brainstem directly, including the parafascicular thalamus (GPePf) and the pedunculopontine nucleus (GPePPN). These projection-defined subpopulations exhibit distinct behavioral functions. GPe-PPN neurons are selectively suppressed at locomotor onset, and bidirectional manipulation of this pathway is sufficient to promote or suppress locomotion. Notably, D2-MSN stimulation upstream of these neurons evokes locomotion, and co-activation of GPePPN pathway blocks this D2-MSN-evoked locomotion, demonstrating a disinhibitory circuit for action stemming from D2-MSNs. In contrast, GPePf neurons are not engaged during locomotion but are selectively recruited during skilled forelimb actions, and their activation disrupts forelimb movements without affecting locomotion. Together, these findings establish the GPe as a basal ganglia output hub composed of modules that mediate distinct behaviors. This organization revises canonical models of the indirect pathway by demonstrating that D2-MSNs can also facilitate, rather than only suppress, movement depending on the downstream GPe output channels they engage. In briefThe external globus pallidus (GPe), classically considered a relatively homogeneous relay within the indirect basal ganglia pathway, is revealed here as a major basal ganglia output hub. Distinct GPe subpopulations, defined by transcriptomic identity and projection target, form parallel channels to cortical, thalamic and brainstem structures with action-specific functions. These findings uncover a disinhibitory mechanism through which D2-MSNs can facilitate behavior, revising canonical models of basal ganglia function. HighlightsBrain-wide mapping reveals the GPe as a major basal ganglia output node GPe contains novel cell types defined by transcriptomic identity and projection specificity Projection-specific GPe circuits differentially control locomotion and skilled forelimb actions D2-MSNs can disinhibit downstream targets via specific GPe projections and promote action.

neuroscience↗

bioRxiv2026

Topographic structure and function of locus coeruleus norepinephrine neurons

Norepinephrine (NE) is released throughout most of the central nervous system by neurons in the locus coeruleus (LC). We found a relationship between the morphologies, gene expression, and activity of LC-NE neurons in mice. Axonal projections of individual neurons were extensive but largely confined to subsets of brain regions. Axonal projections and graded gene expression correlated with locations of cell bodies in LC. In a behavioral task requiring ongoing learning from actions, neurons in dorsal LC projecting to the cerebral cortex were excited when mice made a different choice from the previous one and by reward prediction errors, a signal driving learning. Background activity of neurons in ventral LC was higher when mice ignored stimuli indicating potential reward availability. These observations reveal a topographically organized structure and function of a neurotransmitter system and show that it contains learning signals for flexible behavior.

neuroscience↗

bioRxiv2026

Thalamocortical network dynamics in focal epilepsy: SEEG investigation

Thalamic neuromodulation is clinically effective in drug{-}resistant epilepsy, suggesting critical contributions of the thalamus to the epileptogenic process. However, the underlying electrophysiologic mechanisms remain poorly characterized. Converging evidence implicates the thalamus in shaping large{-}scale functional interactions across the cortex. We hypothesized that ictal changes in thalamic activity track cortical network dynamics associated with seizure propagation. We analyzed stereo{-}electroencephalography recordings from 16 patients with focal epilepsy (255 seizures) with simultaneous sampling of the thalamus (anterior nucleus, N=14; pulvinar, N=11) and cortex. Cortical regions of interest included the seizure onset zone (SOZ), surrounding cortices (near{-}SOZ), and control regions from the contralateral hemisphere. We characterized seizure dynamics across spatial scales, from local activity within each region to network{-}level, inter{-}regional interactions. Local activity was decomposed into its periodic (oscillatory) and aperiodic components. Network interactions were characterized by directed functional connectivity computed with a multivariate method. Seizures were associated with increased broadband power (a proxy for neuronal population firing rates) and low{-}frequency rhythmic activity across the thalamocortical network relative to interictal baseline levels. In contrast, consistent changes in aperiodic slope (a putative marker of excitation{-}inhibition balance) were specific to the thalamus, which showed an early and sustained steepening (i.e., more negative slope). While local rhythms were heterogeneous across the canonical frequency bands, inter{-}regional interactions predominantly involved the beta band (13{-}30 Hz). Shortly after onset, both forward outflow from SOZ to near{-}SOZ and feedback inflow in the reverse direction were increased. These bidirectional effects were expressed via both a direct cortico{-}cortical pathway and an indirect transthalamic route, operating in parallel. These dynamics were further stratified based on seizure subtypes, leveraging the fact that there was minimal propagation of ictal activity to the near{-}SOZ in subclinical seizures. The ictal drop in thalamic aperiodic slope was primarily observed in clinical seizures. At the network level, whereas SOZ[->]near{-}SOZ outflow was present across seizure types, reverse feedback was particularly enhanced in clinical seizures. Multivariable regression showed that the degree of thalamic slope steepening uniquely tracked seizure{-}to{-}seizure fluctuations in the strength of near{-} SOZ[->]SOZ feedback, and further predicted seizure durations. Together these findings highlight thalamic aperiodic slope as an index of cortical network dynamics linked to seizure propagation, with potential clinical utility for further development of physiology{-}informed precision neuromodulation.

neuroscience↗

bioRxiv2026

The Caudate Nucleus Exhibits Distinct Pathology and Cell Type-Specific Responses Across Alzheimer's Disease

A{beta} presence in the caudate nucleus (Ca) partially defines Thal stage III in Alzheimers disease (AD), but little is known about ADs cellular impact on the region. Leveraging a public basal ganglia taxonomy of cellular populations, we generated a cellular resolution atlas of AD-associated pathological changes in Ca. Unlike cortex, we found that Ca AD pathology is dominated by two key features: phosphorylated tau (pTau)-containing neuropil threads enriched near oligodendrocytes in white matter tracts and amyloid-{beta} diffuse plaques enriched in gray matter. Although AD pathology in affected cortical regions results in neuronal loss, we find no AD-driven reductions in neuron proportions in Ca. However, there were observable changes in multiple cellular populations. Protoplasmic astrocytes and FLT1+/IL1B+ microglia increased in abundance with global pTau levels. We also observe gene expression changes in fast-spiking PTHLH-PVALB interneurons indicative of disrupted signaling pathways and altered intrinsic physiological properties. This work provides a cellular-resolution framework for understanding AD pathology in Ca.

neuroscience↗

bioRxiv2025

Tissue-to-Bytes: A Catalytic Digital Twin Platform for Consortium-Scale Integration of Single-Cell Omics Data in BRAIN Initiative Cell Atlas Network

Monolithic Electronic Health Record (EHR) architectures remain fundamentally misaligned with high-resolution, specialty-specific clinical workflows, contributing to significant physician burnout and challangies in secondary use of data. This study introduces the Enterprise Health Twin (EHT) framework, a paradigm grounded in the Digital Twin concept, with the goal to transform static clinical ledgers into dynamic decision-support systems. The EHT establishes continuous bidirectional feedback (feed-forward ingestion and feed-backward decision support) between the physical entities of clinical workflows and the digital counterparts of interfaces reflecting the evolving states of the workflow, for each individual patient in the EHT. We conceptualized, prototyped, and operationalized the EHT framework for epilepsy care for seven years, in production, at the point of care. Deployed at the Epilepsy Center of the University of Texas Health Science Center at Houston, a [~]400% increase productivity has been achieved in specialized surgical evaluation throughput without additional staffing. The EHT achieved de novo capture of ontology-anchored structured data at the point of care, mitigating cognitive load while growing the volume of high-resolution, annotated longitudinal datasets for clinical research, and driving an increase of care velocity in a learning healthcare system.

neuroscience↗

bioRxiv2025

Integrin β1-Talin1 at focal adhesions underpin uncontrolled endothelial cell enlargement in live cerebral cavernous malformation vasculature

Cerebral cavernous malformations (CCMs) are vascular anomalies caused by loss of CCM gene function and consequent hyperactivation of MEKK3-KLF2/4 signaling in endothelial cells. Excess integrin {beta}1 activity has been associated with lesion growth, yet the precise mechanistic and biomechanical roles of the integrin-KLF2/4 hierarchy in CCM cellular pathogenesis are not fully understood. Using live imaging of endothelial Vinculin in Ccm1-deficient zebrafish, we demonstrate excessive, mechanically active focal adhesions in an in vivo model of CCM pathology. We validate this in CCM1-deficient endothelial cells and show a redistribution of mechanical tension from cell-cell junctions to focal adhesions. Genetic deletion of Talin1 to decouple focal adhesions from the cell cortex and inhibit integrin {beta}1 signaling demonstrates the integrin {beta}1-Talin1 complex is essential for vascular malformations in ccm1 mutants by driving endothelial cell enlargement. We show integrin {beta}1-Talin1 act independent or downstream of KLF2/4, rather than upstream as previously suggested. Thus, we reposition the role of integrin {beta}1-Talin1 in CCM pathogenesis, demonstrating an essential function in driving cell enlargement, which underpins lesion growth.

cell biology↗

bioRxiv2025

HCN channels reveal conserved and divergent physiology in supragranular pyramidal neurons in primate species

The physiological properties of human and rodent neurons differ, yet the extent to which these differences reflect human specializations is often unclear. Compared with their rodent counterparts, human supragranular pyramidal neurons possess enriched HCN-channel-dependent intrinsic membrane properties and a related sensitivity to synaptic inputs containing delta/theta band frequencies. We tested whether other primate species possess enriched HCN-channel dependent membrane properties. We found ubiquitous HCN1 subunit gene expression in supragranular glutamatergic neurons across New World Monkeys, Old-World Monkeys, and great apes in single nucleus RNA-sequencing datasets. Using Patch-seq recordings from acute and cultured brain slices, we found robust HCN-dependent physiological properties in supragranular pyramidal neurons in a species of New-World monkey (Saimiri sciureus) and two species of Old-World Monkey (Macaca mulatta, Macaca nemestrina). In both human and macaque neocortex, HCN-related intrinsic properties increased in magnitude with increasing laminar depth, especially in one transcriptomic cell type. Within this type, HCN dependent properties were more pronounced in macaque than human neurons. These findings indicate that HCN-governed membrane properties and sensitivity to delta/theta band frequencies are roughly conserved in supragranular pyramidal neurons across at least 36 million years of primate evolution.

neuroscience↗

bioRxiv2025

Technical and biological sources of noise confound multiplexed enhancer AAV screening

Cis-acting regulatory enhancer elements are valuable tools for gaining cell type-specific genetic access. Leveraging large chromatin accessibility atlases, putative enhancer sequences can be identified and deployed in adeno-associated virus (AAV) delivery platforms. However, a significant bottleneck in enhancer AAV discovery is charting their detailed expression patterns in vivo, a process that currently requires gold-standard one-by-one testing. Here we present a barcoded multiplex strategy for screening enhancer AAVs at cell type resolution using single cell RNA sequencing and taxonomy mapping. We executed a proof-of-concept study using a small pool of validated enhancer AAVs expressing in a variety of neuronal and non-neuronal cell types across the mouse brain. Unexpectedly, we encountered substantial technical and biological noise including chimeric packaging products, necessitating development of novel techniques to accurately deconvolve enhancer expression patterns. These results underscore the need for improved methods to mitigate noise and highlight the complexity of enhancer AAV biology in vivo.

neuroscience↗

bioRxiv2024

Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (ttn.2) Variants

BackgroundTruncating variants (TTNtv) in the TTN gene, encoding the giant sarcomeric protein titin, cause a range of human cardiac and skeletal muscle disorders of varying penetrance and severity. The effects of variant location on clinical manifestations are incompletely understood. MethodsWe generated six zebrafish lines carrying tv in the ttn.2 gene at the Z-disk, I-band, A-band, and M-band titin regions. Expression of titin transcripts was evaluated using qPCR. Phenotype analysis was performed during embryonic development and in adult hearts. ResultsUsing location-specific primers, we found a significant reduction of Z-disk and I-band ttn.2 transcripts in all homozygous embryos but levels of A-band and M-band transcripts were reduced only in lines with truncations distal to the cronos promoter. Homozygous embryos uniformly died by 7-10 days post fertilization with marked impairment of cardiac morphology and function. Skeletal muscle motility and sarcomere organization were more disrupted in mutants with truncations distal to the cronos promoter compared to those proximal. The most C-terminal line (e232), which lacked only the titin kinase and M-band regions, differed from other lines, with homozygous embryos showing incorporation of truncated Ttn.2/Cronos protein and normal sarcomere assembly, but selective degradation of fast skeletal muscle sarcomeres. Heterozygous embryos were phenotypically indistinguishable from wild-type. High-frequency echocardiography in adult heterozygous fish showed reduced ventricular contraction under resting conditions in A-band mutants. Heterozygous Z-disk and I-band mutants had no significant baseline impairment but were unable to augment ventricular contraction in response to acute adrenaline exposure, indicating a lack of cardiac reserve. ConclusionsOur data suggest that cardiac and skeletal muscle dysfunction associated with truncating ttn.2 variants is influenced by age, variant location, and the amount of functional titin protein. The distinctive phenotype associated with distal C-terminal truncations may reflect different requirement for C-terminal titin for maintenance of fast, slow and cardiac muscle sarcomeres.

cell biology↗

bioRxiv2024

Inhibition of the RNA Regulator HuR mitigates spinal cord injury by potently suppressing post-injury neuroinflammation

BackgroundNeuroinflammation plays a significant role in promoting secondary tissue injury after spinal cord trauma. Within minutes after spinal cord injury (SCI), microglia and astrocytes become activated and produce inflammatory mediators such as TNF-, IL-6, iNOS and COX-2 which induce tissue injury through cytotoxicity, vascular hyperpermeability, and secondary ischemia. The inflammatory cascade is amplified by chemokines such as CCL2 and CXCL1 that promote recruitment of peripheral inflammatory cells into the injured spinal cord. HuR is a key post-transcriptional RNA regulator that controls glial expression of many pro-inflammatory factors by binding to adenylate- and uridylate-rich elements in 3 untranslated regions of the mRNA. SRI-42127 is a small molecule inhibitor that blocks HuR nucleocytoplasmic translocation, a process critical for its regulatory function. The goal of this study was to assess the potential of SRI-42127 for suppressing neuroinflammation after SCI and improving functional outcome. MethodsAdult female mice underwent a contusion injury at the T10 level. SRI-42127 or vehicle was administered intraperitoneally starting 1 h after injury and up to 5 days. Locomotor function was assessed by open field testing, balance beam and rotarod. Immunohistochemistry was used to assess lesion size, neuronal loss, myelin sparing, microglial activation and HuR localization. Molecular analyses of spinal cord and peripheral tissues for expression of inflammatory mediators included qPCR, immunohistochemistry, ELISA, or western blot. Post-SCI pain was assessed by the mouse grimace scale. ResultsSRI-42127 significantly attenuated loss of locomotor function and post-SCI pain. Histologic correlates to these beneficial effects included reduced lesion size, neuronal loss, and an increase in myelin sparing. There was reduced microglial activation at the epicenter with concomitant attenuation of HuR nucleocytoplasmic translocation. Molecular analysis revealed a striking reduction of pro-inflammatory mediators at the epicenter including IL-6, MMP-12, IL-1{beta}, TNF-, iNOS, COX-2, and chemokines CCL2, CXCL1, and CXCL2. Suppression of inflammatory responses extended peripherally including serum, liver, and spleen. ConclusionTargeting HuR after SCI is a viable therapeutic approach for suppressing neuroinflammatory responses after tissue injury and improving functional outcome.

neuroscience↗

bioRxiv2024

Continuous cell type diversification throughout the embryonic and postnatal mouse visual cortex development

The mammalian cortex is composed of a highly diverse set of cell types and develops through a series of temporally regulated events that build out the cell type and circuit foundation for cortical function. The mechanisms underlying the development of different cell types remain elusive. Single-cell transcriptomics provides the capacity to systematically study cell types across the entire temporal range of cortical development. Here, we present a comprehensive and high-resolution transcriptomic and epigenomic cell type atlas of the developing mouse visual cortex. The atlas was built from a single-cell RNA-sequencing dataset of 568,674 high-quality single-cell transcriptomes and a single-nucleus Multiome dataset of 194,545 high-quality nuclei providing both transcriptomic and chromatin accessibility profiles, densely sampled throughout the embryonic and postnatal developmental stages from E11.5 to P56. We computationally reconstructed a transcriptomic developmental trajectory map of all excitatory, inhibitory, and non-neuronal cell types in the visual cortex, identifying branching points marking the emergence of new cell types at specific developmental ages and defining molecular signatures of cellular diversification. In addition to neurogenesis, gliogenesis and early postmitotic maturation in the embryonic stage which gives rise to all the cell classes and nearly all subclasses, we find that increasingly refined cell types emerge throughout the postnatal differentiation process, including the late emergence of many cell types during the eye-opening stage (P11-P14) and the onset of critical period (P21), suggesting continuous cell type diversification at different stages of cortical development. Throughout development, we find cooperative dynamic changes in gene expression and chromatin accessibility in specific cell types, identifying both chromatin peaks potentially regulating the expression of specific genes and transcription factors potentially regulating specific peaks. Furthermore, a single gene can be regulated by multiple peaks associated with different cell types and/or different developmental stages. Collectively, our study provides the most detailed dynamic molecular map directly associated with individual cell types and specific developmental events that reveals the molecular logic underlying the continuous refinement of cell type identities in the developing visual cortex.

neuroscience↗

bioRxiv2024

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, {beta}-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

neuroscience↗

bioRxiv2024

Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque

Experimental access to cell types within the mammalian spinal cord is severely limited by the availability of genetic tools. To enable access to lower motor neurons (LMNs) and LMN subtypes, we generated single cell multiome datasets from mouse and macaque spinal cords and discovered putative enhancers for each neuronal population. We cloned these enhancers into adeno-associated viral vectors (AAVs) driving a reporter fluorophore and functionally screened them in mouse. We extensively characterized the most promising candidate enhancers in rat and macaque and developed an optimized pan LMN enhancer virus. Additionally, we generated derivative viruses expressing iCre297T recombinase or ChR2-EYFP for labeling and functional studies, and we created a single vector with combined enhancer elements to achieve simultaneous labeling of layer 5 extratelencephalic projecting (ET) neurons and LMNs. This unprecedented LMN toolkit will enable future investigations of cell type function across species and potential therapeutic interventions for human neurodegenerative diseases.

neuroscience↗

bioRxiv2024

The transcriptomic and spatial organization of telencephalic GABAergic neuronal types

The telencephalon of the mammalian brain comprises multiple regions and circuit pathways that play adaptive and integrative roles in a variety of brain functions. There is a wide array of GABAergic neurons in the telencephalon; they play a multitude of circuit functions, and dysfunction of these neurons has been implicated in diverse brain disorders. In this study, we conducted a systematic and in-depth analysis of the transcriptomic and spatial organization of GABAergic neuronal types in all regions of the mouse telencephalon and their developmental origins. This was accomplished by utilizing 611,423 single-cell transcriptomes from the comprehensive and high-resolution transcriptomic and spatial cell type atlas for the adult whole mouse brain we have generated, supplemented with an additional single-cell RNA-sequencing dataset containing 99,438 high-quality single-cell transcriptomes collected from the pre- and postnatal developing mouse brain. We present a hierarchically organized adult telencephalic GABAergic neuronal cell type taxonomy of 7 classes, 52 subclasses, 284 supertypes, and 1,051 clusters, as well as a corresponding developmental taxonomy of 450 clusters across different ages. Detailed charting efforts reveal extraordinary complexity where relationships among cell types reflect both spatial locations and developmental origins. Transcriptomically and developmentally related cell types can often be found in distant and diverse brain regions indicating that long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons. Additionally, we find various spatial dimensions of both discrete and continuous variations among related cell types that are correlated with gene expression gradients. Lastly, we find that cortical, striatal and some pallidal GABAergic neurons undergo extensive postnatal diversification, whereas septal and most pallidal GABAergic neuronal types emerge simultaneously during the embryonic stage with limited postnatal diversification. Overall, the telencephalic GABAergic cell type taxonomy can serve as a foundational reference for molecular, structural and functional studies of cell types and circuits by the entire community.

neuroscience↗

bioRxiv2024

Sex-specific regulation of the cardiac transcriptome by the protein phosphatase 2A regulatory subunit B55α

1.Protein phosphatase 2A (PP2A) regulatory subunit B55 has been implicated in the transcriptional regulation of cardiac growth and fibrosis by suppressing HDAC5/MEF2 signalling in cardiomyocytes. We created and characterised two mouse models with global or cardiomyocyte-specific disruption of the gene encoding B55 (Ppp2r2a) to conduct the first detailed exploration of B55 in the heart. Global homozygous B55 knockout mice died in utero, while heterozygous mice had thinner left ventricular walls at 12 months, an effect more pronounced in males. At 10-12 weeks of age, cardiomyocyte-specific B55 knockout mice displayed normal cardiac morphology with increased left ventricular collagen deposition, identifying B55 as a negative regulator of cardiac fibrosis. Gene expression analyses revealed extensive remodelling of the cardiac transcriptome in male but not female mice, identifying a sexually dimorphic role for B55 in cardiac transcriptional regulation. These findings provide a basis for future work investigating B55 in cardiac stress settings.

physiology↗

bioRxiv2024

Epithelial IL-2 is critical for NK cell-mediated cancer immunosurveillance in mammary glands

Interleukin 2 (IL-2) is the first identified cytokine and its interaction with receptors has been known to shape the immune responses in many lymphoid or non-lymphoid tissues for more than four decades. Active T cells are the primary cellular source for IL-2 production and epithelial cells have never been considered the major cellular source of IL-2 under physiological conditions. It is, however, tempting to speculate that epithelial cells could potentially express IL-2 that regulates the intricate interactions between epithelial cells and lymphocytes. Datamining our recently published single-cell RNAseq in the mouse mammary gland identified IL-2 expression in mammary epithelial cells, which is induced by prolactin via the STAT5 signaling pathway. Furthermore, epithelial IL-2 plays a crucial role in maintaining the physiological functions of natural killer (NK) cells within the mammary glands. IL-2 deletion in the mammary epithelial cells leads to a significant reduction in the number and function of NK cells, which in turn results in defective immunosurveillance, expansion of luminal epithelial cells, and tumor development. Interestingly, T cells in the mammary glands are not changed, indicating the specific regulation of NK cells by epithelial IL-2 production. In agreement, we also found that human epithelial cells express IL-2 and NK cells express the highest level of IL2RB among all the immune cells. Here, we provide the first evidence that epithelial cells produce IL-2, which is critical for maintaining the physiological functions of NK cells in immunosurveillance.

immunology↗