Biology subjects

Spencer, C.

Publications and source records attributed to Spencer, C..

8 recordsLinked to original sources

bioRxiv2026

Distinct functions of PBRM1 and BAP1 reconcile the course of kidney cancer evolution and disease progression

Clear cell renal cell carcinoma (ccRCC) progresses along two predominant evolutionary trajectories, defined by PBRM1 ([~]40%) or BAP1 ([~]15%) mutations on a VHL-inactivated background. They have distinct patterns of evolutionary tempo and mode, and vastly different clinical outcomes, yet the underlying genotype-specific molecular phenotypic programmes are unknown. We established a patient-derived preclinical model biobank that captures the genetic diversity of ccRCC. Through integrative analyses of preclinical models and tumour bulk and single cell profiling, we identified transcriptional and epigenetic changes specific to PBRM1- and BAP1-driven ccRCC. Modelling PBRM1 loss in vitro demonstrates that it reinforces renal lineage identity and maintains progenitor-like cell state. In contrast, BAP1 loss drives inflammatory signalling and chromosomal instability. These insights reconcile the distinct evolutionary modes (branched versus punctuated), tempo (slow versus fast) and clinical outcomes associated with PBRM1 and BAP1 mutations, respectively, establishing a framework for patient stratification and genotype-directed therapeutic development.

cancer biology↗

bioRxiv2025

Axo-Axonic Synapses on Descending Neurons in the Drosophila Ventral Nerve Cord

Axo-axonic synapses can veto, amplify, or synchronize spikes, yet their circuit-scale logic is unknown. Using the complete electron-microscopy connectome of the adult male Drosophila, we charted every axo-axonic input onto the 1,314 descending neurons that carry brain commands to the ventral nerve cord. By definition, any synapse connected to a descending neuron within the cord is axo-axonic. Thus, we uncovered the ascending-descending and interneurons-descending axo-axonic relationship. Neurons with many partners (high-degree) integrate into the network without clustering into an interconnected rich-club of hubs. We identified an octet of ascending neurons (AN08B098) whose axo-axonic input to the Giant Fibers (DNp01) predicted modulation of the escape circuit. Immunostaining confirms their cholinergic identity, while optogenetic activation confirmed that this excitatory cohort increases DNp01 excitability, validating connectome-derived rules. Our work delivers a map of axo-axonic wiring in a complete ventral nerve cord connectome and provides constraints for models of fast motor control.

neuroscience↗

bioRxiv2025

KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

neuroscience↗

bioRxiv2024

Human formin FHOD3-mediated actin elongation is required for sarcomere integrity in cardiomyocytes

Contractility and cell motility depend on accurately controlled assembly of the actin cytoskeleton. Formins are a large group of actin assembly proteins that nucleate and elongate new actin filaments. Some formins may cap filaments while others sever or bundle filaments. The Formin HOmology Domain-containing protein (FHOD)-family of formins is critical to the formation of the fundamental contractile unit in muscle, the sarcomere. Specifically, mammalian FHOD3L plays an essential role in cardiomyocytes. Despite our knowledge of FHOD3Ls importance in cardiomyocytes, its biochemical and cellular activities remain poorly understood. It was proposed that FHOD-family formins act by capping and bundling, as opposed to assembling new filaments. Here, we demonstrate that FHOD3L nucleates actin and rapidly but briefly elongates filaments after temporarily pausing elongation. We designed function-separating mutants that enabled us to distinguish which biochemical roles are required in the cell. We found that human FHOD3Ls elongation activity, but not its nucleation, capping, or bundling activity, is necessary for proper sarcomere formation and contractile function in neonatal rat ventricular myocytes. The results of this work provide new insight into the mechanisms by which formins build specific structures and will contribute to knowledge regarding how cardiomyopathies arise from defects in sarcomere formation and maintenance.

cell biology↗

bioRxiv2022

Classification of electrically-evoked compound action potentials in the parkinsonian subthalamic nucleus of non-human primates

Electrically evoked compound action potentials (ECAPs) generated in the subthalamic nucleus (STN) contain features that may be useful for titrating deep brain stimulation (DBS) therapy for Parkinsons disease. Delivering a strong therapeutic effect with DBS therapies, however, relies on selectively targeting neural pathways to avoid inducing side effects. In this study, we investigated the spatiotemporal features of ECAPs in and around the STN across parameter sweeps of stimulation current amplitude, pulse width, and electrode configuration, and used a linear classifier of ECAP responses to predict electrode location. Four non-human primates were implanted unilaterally with either a directional (n=3) or non-directional (n=1) DBS lead targeting the sensorimotor STN. ECAP responses were characterized by primary features (within 1.6 ms after a stimulus pulse) and secondary features (between 1.6-7.4 ms after a stimulus pulse). Using these ECAP features, a linear classifier was able to accurately differentiate electrodes within the STN versus dorsal to the STN in all four subjects. ECAP responses varied systematically with recording and stimulating electrode locations, which provides a subject-specific neuroanatomical basis for selecting electrode configurations in the treatment of Parkinsons disease with DBS therapy.

neuroscience↗

bioRxiv2021

Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration disrupting daytime locomotion

Inflammation is known to disrupt normal behavior, yet the underlying neuroimmune interactions remain elusive. Here, we investigated whether inappropriate macrophage-evoked inflammation alters CNS control of daily-life animal locomotion using a set of zebrafish mutants selected for specific macrophage dysfunction and microglia deficiency. Large-scale genetic and computational analyses revealed that NOD-like receptor nlrc3l mutants are capable of normal motility and visuomotor response, but preferentially swim less in the daytime, suggesting low motivation rather than physical impairment. Examining their brain activities and structures implicate impaired dopaminergic descending circuits, where neutrophils abnormally infiltrate. Furthermore, neutrophil depletion recovered daytime locomotion. Restoring wild-type macrophages reversed behavioral and neutrophil aberrations, while three other microglia-lacking mutants failed to phenocopy nlrc3l mutants. Overall, we reveal how peripheral inflammatory macrophages with elevated pro-inflammatory cues (including il1b, tnfa, cxcl8a) in the absence of microglia co-opt neutrophils to infiltrate the brain, thereby enabling local modulation of neural circuits affecting spontaneous locomotion.

immunology↗

bioRxiv2017

Phenome-wide association studies (PheWAS) across large "real-world data" population cohorts support drug target validation

Phenome-wide association studies (PheWAS), which assess whether a genetic variant is associated with multiple phenotypes across a phenotypic spectrum, have been proposed as a possible aid to drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we evaluate whether PheWAS can inform target validation during drug development. We selected 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate drug targets for common disease therapeutic indications. We independently interrogated these SNPs through PheWAS in four large \"real-world data\" cohorts (23andMe, UK Biobank, FINRISK, CHOP) for association with a total of 1,892 binary endpoints. We then conducted meta-analyses for 145 harmonized disease endpoints in up to 697,815 individuals and joined results with summary statistics from 57 published GWAS. Our analyses replicate 70% of known GWAS associations and identify 10 novel associations with study-wide significance after multiple test correction (P<1.8x10-6; out of 72 novel associations with FDR<0.1). By leveraging directionality and point estimate of the effect sizes, we describe new associations that may predict ADEs, e.g., acne, high cholesterol, gout and gallstones for rs738409 (p.I148M) in PNPLA3; or asthma for rs1990760 (p.T946A) in IFIH1. We further propose how quantitative estimates of genetic safety/efficacy profiles can be used to help prioritize candidate targets for a specific indication. Our results demonstrate PheWAS as a powerful addition to the toolkit for drug discovery.\n\nOne Sentence SummaryMatching genetics with phenotypes in 800,000 individuals predicts efficacy and on-target safety of future drugs.

genetics↗

bioRxiv2017

Inferring adaptive gene-flow in recent African history

Gene-flow from an ancestrally differentiated group has been shown to be a powerful source of selectively advantageous variants. To understand whether recent gene-flow may have contributed to adaptation among humans in sub-Saharan Africa, we applied a novel method to identify deviations in ancestry inferred from genome-wide data in 48 populations. Among the signals of ancestry deviation that we find in the Fula, an historically pastoralist ethnic group from the Gambia, are the region that encodes the lactose persistence phenotype, LCT/MCM6, which has the highest proportion of Eurasian ancestry in the genome. The region with the lowest proportion of non-African ancestry is across DARC, which encodes the Duffy null phenotype and is protective for Plasmodium vivax malaria. In the Jola from the Gambia and a Khoesan speaking group from Namibia we find multiple regions with inferred ancestry deviation including the Major Histocompatibility Complex. Our analysis shows the potential for adaptive gene-flow in recent human history.

evolutionary biology↗