Biology subjects

Nelson, A. C.

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

At least 19 recordsLinked to original sources

bioRxiv2026

Interrogation of noncoding schizophrenia risk variants using CRISPR-based functional genomics

Schizophrenia (SCZ) is a highly heritable complex disorder influenced by coding and noncoding genetic variation. Its genetic causes, particularly those involving noncoding variation, are largely unknown. High-throughput CRISPR screens enable dissection of disease-associated loci and identification of noncoding regulatory elements and variants that modulate gene expression. We screened SCZ GWAS loci linked to genes that are also associated in whole-exome sequencing studies to identify regulatory elements and variants impacting expression of disease-relevant genes. We used CRISPRi paired with HCR-FlowFISH to epigenetically silence 333 putative regulatory elements and measure the downstream effects on gene expression of causal SCZ genes, FAM120A, SV2A, and STAG1, in iPSCs and iPSC-derived neurons (iNeurons). We identified 78 regulatory elements that significantly alter expression of a SCZ gene, including noncoding enhancers/silencers as well as promoters of genes and lncRNAs. Pooled prime editing screens interrogated noncoding variant influence on gene expression for SCZ-associated variants and uncharacterized common variants from diverse population studies. We find that a common variant in the promoter of SV2A, rs112851681:A>G (MAF = 3.56%, 1000 Genomes) enhances transcriptional activity in iPSCs and iNeurons. These findings show distinct noncoding mechanisms that map within GWAS signals, and provide a path forward for interrogating noncoding regulatory elements and variants in disease loci.

genomics↗

bioRxiv2026

Social hierarchy assays measure independent features of competitive ability

Social hierarchies are a nearly universal feature of animal groups, but whether dominance reflects a single generalized trait or a collection of context-specific competitive abilities remains unclear. Here, we assess social hierarchy in three strains of laboratory mice (BALB/c, C57BL/6, and Shank3B knockouts) of both sexes using three established paradigms: the tube test, the warm spot assay, and the void spot assay. Hierarchies emerged in all strains and both sexes across all three assays, but how animals established rank differed markedly by strain and sex. In the tube test, Shank3b-/- knockout females, but not males, lacked the winner effects seen in wild-type mice, indicating that the ability to build a winning streak depends on social recognition in a sex-specific manner. In the warm spot assay, females formed stronger hierarchies than males, particularly among mice on a C57BL/6 background, with high-ranking females actively displacing others from the warm platform. In the void spot assay, BALB/c mice of both sexes frequently displayed territory-marking behavior, a pattern that was less common in the other strains. Overall, individual rank rarely generalized across domains, despite high trial-to-trial repeatability for individuals within each assay. Together, these findings indicate that mice behave as dominance specialists rather than generalists, with strain- and sex-specific strategies for establishing rank in different competitive contexts, suggesting that distinct neural circuits likely underlie these separable components of competitive ability.

animal behavior and cognition↗

bioRxiv2025

Mathematical Modeling of Bone Remodeling after Surgical Menopause

Osteoporosis is a skeletal pathology characterized by decreased bone mass and structural deterioration resulting from an imbalance in bone metabolic processes. Estrogen deficiency in postmenopausal women leads to an increased risk of osteoporosis, while women who have undergone complete oophorectomies display an even higher risk due to the sudden decrease in estrogen. Some evidence indicates that bone loss slows in the period beyond 15 years after surgery; however, there is substantial uncertainty in clinical data. To explore the effects of surgically induced menopausal transition, here we propose a mathematical model for the bone cell dynamical responses to sudden estrogen deficiency, which extends an existing model for osteoporosis due to aging and natural menopause. Using data on the key impacts observed in female mice and humans after bilateral oophorectomy, this new model considers the role of osteocytes embedded within the bone mineralized matrix in regulating osteoclastogenesis, which results in increased bone resorption after surgical menopause. The values of model parameters in natural and surgical menopause were estimated from aggregated human clinical data from existing longitudinal studies. The new model effectively captures the previously unmodeled increase in bone loss during the first 15 years post-surgical menopause and the rebound in bone mineral density in the long-term. With this model, effects of treatments on targeting osteocyte dynamics could be explored in the future.

systems biology↗

bioRxiv2025

Tumor Cells Enriched for Interferon and Inflammatory Programs Pre-Exist in High Grade Serous Ovarian Cancer and are Proportionately Significantly Increased Post Chemotherapy

Drug-tolerant, high-grade serous ovarian cancer (HGSOC) cells that persist after first-line chemotherapy and subsequently relapse often retain sensitivity to secondary treatment, suggesting a therapeutic window before stable chemoresistance emerges. We performed single-cell RNA sequencing (scRNA-seq) on seven matched pairs of tumors, collected pre- and post-chemotherapy, to define vulnerabilities in these reversibly-resistant cells. Treatment induced a marked enrichment of tumor and stromal cell populations expressing correlated interferon (IFN) and inflammatory (IFM) gene signatures, with a concurrent depletion of proliferation-related and MYC-associated states in the tumor cells. Cross-cohort single cell sequencing analysis of >130 treatment-naive tumors revealed heterogeneity in the abundance of IFN/IFM-expressing cells. Multiplex immunofluorescence imaging of IFN-stimulated gene (ISG) products confirmed the presence of spatially clustered ISG-positive tumor cells in all cases, as well as in serous tubal intraepithelial carcinomas (STIC lesions), the presumptive HGSOC precursors. ISG expression correlated strongly with ORF1P, a protein encoded by the endogenous retrotransposon LINE1. These data suggest that early oncogenic events drive LINE1 derepression and innate immune activation, establishing an IFN-rich transcriptional state that persists in tumor subpopulations and is strongly enhanced by chemotherapy.

cancer biology↗

bioRxiv2025

Functional genomics analysis of developing zebrafish and human endoderm reveals highly conserved cis-regulatory modules controlling vertebrate organogenesis

While vertebrate species are superficially diverse, they share key commonalities in terms of overall morphology, and organ configuration and function. Maintenance of these traits during evolution is partially explained by conservation of critical genes governing embryonic development. However, for conserved genes to deliver consistent developmental outcomes between species, similar gene regulatory programmes and gene expression patterns must also be maintained. The endoderm germ layer makes major contributions to the respiratory and gastrointestinal tracts, and associated organs including liver and pancreas. We used functional genomics approaches to identify highly conserved endodermal cis-regulatory modules (CRMs) functioning across the 400 million years of evolution separating zebrafish and humans. Our analyses suggest that there are few endoderm-specific CRMs, with many CRMs governing pancreas developmental also likely acting within the nervous system. Furthermore, these highly conserved CRMs are strongly enriched for binding sites of "neuro-pancreatic" transcription factors governing both pancreas and nervous system development, potentially suggesting function across these distinct organ systems. Additionally, we identify highly conserved CRMs likely participating endodermal patterning of adjacent craniofacial structures and sensory tissues. The highly conserved CRMs we identify are characterised by conserved patterns of transcription factor binding site co-occurrence. However, they are not characterised by rigid arrangement of binding sites, suggesting more complex or individual grammatical rules. Overall, our analyses provide key insights into critical gene regulatory control during vertebrate endoderm organogenesis, and define a compendium of highly conserved CRMs that should be prioritised for analysis of neuro-pancreatic gene transcriptional control, and anterior embryonic patterning.

developmental biology↗

bioRxiv2025

Diurnal Regulation of Urinary Behavior and Gene Expression in Aged Mice

Nocturia, defined as waking one or more times per night to urinate, is a prevalent and burdensome condition with few effective treatments. While the primary risk factor for nocturia is advanced age, few preclinical studies have addressed the pathophysiological mechanisms of nocturia in older subjects. Here, we develop a translational model of nocturia using aging mice and a behavioral paradigm that enables circadian assessment of voluntary urination in group-housed animals. We discovered dampened diurnal regulation of urinary behavior in aged mice compared to adult controls. Molecular analyses revealed disrupted diurnal expression of canonical circadian genes in aged mouse kidney and bladder tissues. Notably, we identified age-related loss of diurnal regulation of the bladder mechanosensory ion channel, Piezo1, suggesting a potential mechanism linking circadian disruption to altered bladder sensitivity. Our results reveal a role for circadian dysfunction in age-related nocturia and identify Piezo1 as a promising therapeutic target for chronobiological intervention.

physiology↗

bioRxiv2024

Oxytocin neurons signal state-dependent transitions to thermogenesis and behavioral arousal in social and non-social settings.

Core body temperature (Tb) is defended within narrow limits through thermoregulatory behaviors like huddling, nesting, and physical activity as well as autonomic responses like brown fat thermogenesis. While Tb displays regulated fluctuations across different behavioral states and rest/arousal cycles, the neural control of these transitions is poorly understood. Here, we investigate the relationship between oxytocin neurons of the paraventricular hypothalamus (PVNOT) and behavioral and autonomic thermoeffector pathways across physiological states in mice. First, we show that PVNOT neurons are activated during social thermoregulation. We then demonstrate that in vivo PVNOT calcium dynamics align with transitions from rest to thermogenesis and behavioral arousal. Counter to our initial hypothesis, these dynamics were observed in both social and non-social contexts. Using a computer vision model to track thermoeffector pathways, we demonstrate that precisely timed stimulation of PVNOT neurons during low-Tb resting states increases thermogenesis followed by behavioral arousal. We therefore suggest a model in which PVNOT neurons facilitate homeostatic state-dependent transitions in thermo-behavioral states.

neuroscience↗

bioRxiv2024

Characterization and bioinformatic filtering of ambient gRNAs in single-cell CRISPR screens using CLEANSER

Recent technological developments in single-cell RNA-seq CRISPR screens enable high-throughput investigation of the genome. Through transduction of a gRNA library to a cell population followed by transcriptomic profiling by scRNA-seq, it is possible to characterize the effects of thousands of genomic perturbations on global gene expression. A major source of noise in scRNA-seq CRISPR screens are ambient gRNAs, which are contaminating gRNAs that likely originate from other cells. If not properly filtered, ambient gRNAs can result in an excess of false positive gRNA assignments. Here, we utilize CRISPR barnyard assays to characterize ambient gRNA noise in single-cell CRISPR screens. We use these datasets to develop and train CLEANSER, a mixture model that identifies and filters ambient gRNA noise. This model takes advantage of the bimodal distribution between native and ambient gRNAs and includes both gRNA and cell-specific normalization parameters, correcting for confounding technical factors that affect individual gRNAs and cells. The output of CLEANSER is the probability that a gRNA-cell assignment is in the native distribution over the ambient distribution. We find that ambient gRNA filtering methods impact differential gene expression analysis outcomes and that CLEANSER outperforms alternate approaches by increasing gRNA-cell assignment accuracy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/611293v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@165c63dorg.highwire.dtl.DTLVardef@ba0e15org.highwire.dtl.DTLVardef@f2b12eorg.highwire.dtl.DTLVardef@14e6c86_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Identifying the molecular basis for functional divergence of duplicated SOX factors controlling endoderm formation and left-right patterning in zebrafish

Endoderm, one of three primary germ layers of vertebrate embryos, makes major contributions to the respiratory and gastrointestinal tracts and associated organs, including liver and pancreas. In mammals, the transcription factor SOX17 is vital for endoderm organ formation and can induce endoderm progenitor identity. Duplication of ancestral sox17 in the teleost lineage produced the paralogues sox32 and sox17 in zebrafish. Sox32 is required for specification of endoderm and progenitors of the left-right organiser (Kupffers Vesicle, KV), with Sox17 a downstream target of Sox32 that is implicated in further KV development. Phenotypic evidence therefore suggests functional similarities between zebrafish Sox32 and Sox17 and mammalian SOX17. Here, we directly compare these orthologues and paralogues, using the early zebrafish embryo as a biological platform for functional testing. Our results indicate that, unlike Sox32, human SOX17 cannot induce endoderm specification in zebrafish. Furthermore, using hybrid protein functional analyses, we show that Sox32 specificity for the endoderm gene regulatory network is linked to evolutionary divergence in its DNA-binding HMG domain from its paralogue Sox17. Additionally, changes in the C-terminal regions of Sox32 and Sox17 underpin their differing target specificities. Finally, we establish that specific conserved peptides in the C-terminal domain are essential for the role of Sox17 in establishing correct organ asymmetry. Overall, our results illuminate the molecular basis for functional divergence of Sox32 and Sox17 in vertebrate endoderm development and left-right patterning, and the evolution of SoxF transcription factor function.

developmental biology↗

bioRxiv2023

Unleashing the secrets of plant-fungal interactions using a transformation-free confocal staining technique that supports AI-assisted quantitative analysis

Laser scanning confocal microscopys ability to generate high-contrast 3D images has become essential to studying plant-fungal interactions. Techniques such as visualization of native fluorescence, fluorescent protein tagging of microbes, GFP/RFP-fusion proteins, and fluorescent labelling of plant and fungal proteins have been widely used to aid in these investigations. Use of fluorescent proteins have several pitfalls including variability of expression in planta and the requirement of gene transformation. Here we used the unlabeled pathogens Parastagonospora nodorum, Pyrenophora teres f. teres, and Cercospora beticola infecting wheat, barley, and sugar beet respectively, to show the utility of a staining and imaging technique that uses propidium iodide (PI), which stains RNA and DNA, and wheat germ agglutinin labeled with fluorescein isothiocyanate (WGA-FITC), which stains chitin, to visualize fungal colonization of plants. This method relies on the use of KOH to remove the cutin layer of the leaf, increasing its permeability. This permeability allows the staining solution to penetrate and efficiently bind to its targets, resulting in a consistent visualization of cellular structures. We have also used this staining technique in conjunction with machine learning to analyze fungal volume, which indicates the fitness of the pathogen in planta, as well as quantifying nuclear breakdown, an early indicator of programmed cell death (PCD). This technique is simple to use, robust, consistent across host species, and can be applied to any plant-fungal interaction. Therefore, this technique can be used to characterize model systems as well as non-model interactions where transformation is not routine.

plant biology↗

bioRxiv2023

Clinical Significance of the Stromatic Component in Ovarian Cancer: Quantity Over Quality in Outcome Prediction

BackgroundThe tumor stroma is composed of a complex network of non-cancerous cells and extracellular matrix elements that collectively are crucial for cancer progression and treatment response. Within the realm of ovarian cancer, the expression of the stromal gene cluster has been linked to poorer progression-free and overall survival rates. However, in the age of precision medicine and genome sequencing, the notion that the simple measurement of tumor-stroma proportion alone can serve as a biomarker for clinical outcome is a topic that continues to generate controversy and provoke discussion. Our current study reveals that it is the quantity of stroma, rather than its quality, that serves as a clinically significant indicator of patient outcome in ovarian cancer. MethodsThis study leveraged the High-Grade-Serous-Carcinoma (HGSC) cohort of the publicly accessible Cancer Genome Atlas Program (TCGA) along with an independent cohort comprising HGSC clinical specimens in diagnostic and Tissue Microarray formats. Our objective was to investigate the correlation between the Tumor-Stroma-Proportion (TSP) and progression-free survival (PFS), overall survival (OS), and response to chemotherapy. We assessed these associations using H&E-stained slides and tissue microarrays. Our analysis employed semi-parametric models that accounted for age, metastases, and residual disease as controlling factors. ResultsWe found that high TSP (>50% stroma) was associated with significantly shorter progression-free survival (PFS) (p=0.016) and overall survival (OS) (p=0.006). Tumors from patients with chemoresistant tumors were twice as likely to have high TSP as compared to tumors from chemosensitive patients (p=0.012). In tissue microarrays, high TSP was again associated with significantly shorter PFS (p=0.044) and OS (p=0.0001), further confirming our findings. The Area Under the ROC curve for the model predicting platinum was estimated at 0.7644. ConclusionsIn HGSC, TSP was a consistent and reproducible marker of clinical outcome measures, including PFS, OS, and platinum chemoresistance. Assessment of TSP as a predictive biomarker that can be easily implemented and integrated into prospective clinical trial design and adapted to identify, at time of initial diagnosis, patients who are least likely to benefit long-term from conventional platinum-based cytotoxic chemotherapy treatment.

pathology↗

bioRxiv2022

Fecal Microbiota Restoration Modulates the Microbiome in Inflammation-Driven Colorectal Cancer

Chronic inflammation of the colon (colitis) is a known risk factor for inflammatory-driven colorectal cancers (idCRC), and intestinal microbiota has been implicated in the etiology of id-CRC. Manipulation of the microbiome is a clinically viable therapeutic approach to limiting id-CRC. To understand the microbiome changes that occur over time in id-CRC, we used a mouse model of idCRC with the treatment of azoxymethane (AOM) and dextran sodium sulfate (DSS) and measured the microbiome over time using 16S rRNA amplicon sequencing. We included cohorts where the microbiome was restored using cage bedding swapping and where the microbiome was depleted using antibiotics to compare to untreated animals. We identified consistent increases in Akkermansia in mice receiving horizontal microbiome transfer (HMT), while the control cohort had consistent longitudinal increases in Anaeroplasma and Alistipes. Additionally, fecal lipocalin-2 (Lcn-2) concentrations were elevated in unrestored animals compared to restored and antibiotic-treated counterparts following HMT. These observations suggest a potential role for Akkermansia, Anaeroplasma, and Alistipes in regulating colonic inflammation in id-CRC.

microbiology↗

bioRxiv2022

Receptor for Hyaluronan-Mediated Motility (RHAMM) defines an invasive niche associated with tumor progression and predicts poor outcomes in breast cancer patients.

Breast cancer invasion and metastasis result from a complex interplay between tumor cells and the tumor microenvironment (TME). Key oncogenic changes in the TME include aberrant metabolism and subsequent signaling of hyaluronan (HA). Hyaluronan Mediated Motility Receptor (RHAMM, HMMR) is a HA receptor that enables tumor cells to sense and respond to the TME during breast cancer progression. Focused gene expression analysis of an internal breast cancer patient cohort demonstrates increased RHAMM expression correlates with aggressive clinicopathological features. We also develop a 27-gene RHAMM-dependent signature (RDS) by intersecting differentially expressed genes in lymph node positive cases with the transcriptome of a RHAMM-dependent model of cell transformation, which we validate in an independent cohort. We demonstrate RDS predicts for poor survival and associates with invasive pathways. Further analyses using CRISPR/Cas9 generated RHAMM -/- breast cancer cells provide direct evidence that RHAMM promotes invasion in vitro and in vivo. Additional immunohistochemistry studies highlight heterogeneous RHAMM expression, and spatial transcriptomics confirms the RDS emanates from RHAMM-high invasive niches. We conclude RHAMM upregulation leads to the formation of invasive niches, which are enriched in RDS-related pathways that drive invasion and could be targeted to limit invasive progression and improve patient outcomes.

cancer biology↗

bioRxiv2020

Eomesodermin is functionally conserved between zebrafish and mouse in spite of different mutant phenotypic severities, and controls left/right organiser formation via interlocking feedforward loops

The T-box family transcription factor Eomesodermin (Eomes) is present in all vertebrates, with many key roles in the developing mammalian embryo and immune system. Homozygous Eomes mutant mouse embryos exhibit early lethality due to defects in both the embryonic mesendoderm and the extraembryonic trophoblast cell lineage. In contrast, zebrafish lacking the predominant Eomes homologue A (Eomesa) do not suffer complete lethality and can be maintained. This suggests fundamental differences in either the molecular function of Eomes orthologues or the molecular configuration of processes in which they participate. To explore these hypotheses we initially analysed the expression of distinct Eomes isoforms in various cell mouse types. Next we compared the functional capabilities of these murine isoforms compared to zebrafish Eomesa. These experiments provided no evidence for functional divergence. Next we examined the functions of zebrafish Eomesa and other T-box family members expressed in early development, as well as its paralogue Eomesb. Though Eomes is a member of the Tbr1 subfamily we found strong evidence for functional redundancy without complete functional equivalence with the Tbx6 subfamily member Tbx16, known to be absent from eutherians and other mammals. Finally, we analysed the ability of Eomesa to induce zebrafish left-right organiser progenitors (known as dorsal forerunner cells) known to be positively regulated by vgll4l, a gene we had previously shown to be repressed by Eomesa. Here we demonstrate that Eomesa indirectly upregulates vgll4l expression via interlocking feedforward loops, suggesting a role in establishment of left/right asymmetry. Overall these findings demonstrate conservation of Eomes molecular function and participation in similar processes, but differential requirements across evolution due to the expanded complement of T-box factors in teleosts. Our analyses also provide insights into the role of Eomesa in left-right organiser formation in zebrafish. Author summaryRecent studies provide evidence for both shared and unique molecular pathways controlling early development in different vertebrate organisms. The transcription factor Eomesodermin plays essential roles during mammalian development and has potent functional capabilities in zebrafish embryos yet is seemingly dispensable for viability. Here we compared functional contributions of the predominant zebrafish Eomesodermin homologue - Eomesa - with multiple isoforms of mouse Eomesodermin. We found them to be functionally indistinguishable in the early embryo. Surprisingly, a distant relative of Eomesodermin in the zebrafish embryo - Tbx16 - which is absent in mammals shows a degree of functional overlap with Eomesodermin, underscoring the different evolutionary requirements for Eomesodermin in teleosts and mammals. Finally, we demonstrate that Eomesodermin differentially regulates the transcriptional cofactor vgll4l, which plays key roles in formation of the zebrafish left/right organiser, at different stages of development. Thus, our work demonstrates the molecular function of Eomesodermin is likely to be conserved throughout vertebrate evolution despite differences in mutant phenotypes, and reveals regulatory mechanisms controlling left/right asymmetric patterning.

developmental biology↗

bioRxiv2020

Analytical Validation of a COVID-19 qRT-PCR Detection Assay Using a 384-well Format and Three Extraction Methods

The COVID-19 global pandemic is an unprecedented health emergency. Insufficient access to testing has hampered effective public health interventions and patient care management in a number of countries. Furthermore, the availability of regulatory-cleared reagents has challenged widespread implementation of testing. We rapidly developed a qRT-PCR SARS-CoV-2 detection assay using a 384-well format and tested its analytic performance across multiple nucleic acid extraction kits. Our data shows robust analytic accuracy on residual clinical biospecimens. Limit of detection sensitivity and specificity was confirmed with currently available commercial reagents. Our methods and results provide valuable information for other high-complexity laboratories seeking to develop effective, local, laboratory-developed procedures with high-throughput capability to detect SARS-CoV-2.

pathology↗

bioRxiv2020

Inflammation promotes tumor aggression by stimulating stromal cell-dependent collagen crosslinking and stromal stiffening

Collagen deposition and stromal stiffening accompany malignancy, compromise treatment, and promote tumor aggression. Clarifying the molecular nature of and the factors that regulate extracellular matrix stiffening in tumors should identify biomarkers to stratify patients for therapy and therapeutic interventions to improve outcome. We profiled lysyl hydroxylase- and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in more aggressive human breast cancer subtypes with the stiffest stroma. These tissues also harbored the highest number of tumor-associated macrophages (TAM), whose therapeutic ablation not only reduced metastasis, but also concomitantly decreased accumulation of collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme lysyl oxidase had no impact on collagen crosslinking in PyMT mammary tumors, whereas stromal cell targeting did. Consistently, stromal cells in microdissected human tumors expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of a cohort of breast cancer patient biopsies revealed that stromal expression of lysyl hydroxylase two, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening correlated significantly disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumor aggression and identify lysyl hydroxylase two as a novel stromal biomarker. SignificanceWe show infiltrating macrophages induce stromal fibroblast, and not epithelial, expression of collagen crosslinking enzymes that drive tumor stiffening. Stromal enzyme LH2 is significantly upregulated in breast cancer patients with the stiffest stroma, the most trivalent HLCCs and the worst prognosis, underscoring its potential as a biomarker and therapeutic target.

cancer biology↗

bioRxiv2019

Molecular and Circuit Architecture of Social Hierarchy

Social hierarchy is a common organizational structure of animal groups, in which an individuals social status generates an adaptive behavioral state that facilitates interactions with other group members. Although generally stable, the social status of an animal can change, underscoring the plasticity of the underlying neural circuits. Here, we uncover the molecular and biophysical properties of a cortico-thalamic circuit that supports the emergence of hierarchy in mice. We established a robust behavioral paradigm to explore the establishment of hierarchy among groups of unfamiliar males, and identified the mediodorsal thalamus (MDT) and the caudal part of anterior cingulate area (cACC) as brain areas that are differentially activated between dominants and subordinates. Glutamatergic MDT neurons project to inhibitory parvalbumin interneurons of the cACC, and activity levels of both cell types control competitive performance. Synaptic inputs and excitability of MDT neurons undergo dramatic changes according to the animal social status, and single nucleus sequencing identified increased transcription of the voltage gated ion channel Trpm3 in dominant mice, leading to enhanced excitatory transmission in the MDT-cACC circuit. Our data suggest a model in which cellular, molecular and biophysical plasticity in a thalamocortical circuit controls the expression of social status.

neuroscience↗

bioRxiv2019

Fgf-driven Tbx protein activities directly induce myf5 and myod to initiate zebrafish myogenesis

Skeletal muscle derives from dorsal mesoderm that is formed during vertebrate gastrulation. Fibroblast growth factor (Fgf) signalling is known to cooperate with transcription factors of the Tbx family to promote dorsal mesoderm formation, but the role of these proteins in skeletal myogenesis has been unclear. Using the zebrafish, we show that dorsally-derived Fgf signals act through Tbx16 and Tbxta to induce two populations of slow and fast trunk muscle precursors at distinct dorsoventral positions. Tbx16 binds to and directly activates the myf5 and myod genes that are required for commitment to skeletal myogenesis. Tbx16 activity depends on Fgf signalling from the organiser. In contrast, Tbxta is not required for myf5 expression. However, Tbxta binds to a specific site upstream of myod not bound by Tbx16, driving myod expression in the adaxial slow precursors dependent upon Fgf signals, thereby initiating muscle differentiation in the trunk. After gastrulation, when similar muscle cell populations in the post-anal tail are generated from the tailbud, declining Fgf signalling is less effective at initiating adaxial myogenesis, which is instead initiated by Hedgehog signalling from the notochord. Our findings provide insight into the ancestral vertebrate trunk myogenic pattern and how it was co-opted during tail evolution to generate similar muscle by new mechanisms.

developmental biology↗