Biology subjects

Weaver, K. J.

Publications and source records attributed to Weaver, K. J..

8 recordsLinked to original sources

bioRxiv2026

Neuronal FICD shapes motivated behavior through modulation of dopamine receptor dynamics

Motivated behaviors rely on dopaminergic signaling, which in turn depends on the correct folding and trafficking of receptors through the endoplasmic reticulum (ER). Within the ER, the AMPylase enzyme FICD acts as a molecular rheostat through its modification of the chaperone BiP, dynamically tuning the organelle's responsiveness to folding perturbations and cellular stress. While the biochemistry of FICD is well-established, its role in complex animal behavior remains poorly understood. Here, we identify FICD as a conserved contributor to the generation of motivated behavior. In Drosophila, pan-neuronal knockdown of dFic significantly reduces feeding, spontaneous locomotion, and reward-seeking behavior. These alterations occur without disrupting circadian architecture, motor capacity, or homeostatic hunger, indicating a specific loss of motivational drive. Depleting dFic within subsets of dopamine receptor-expressing (Dop1R1) neurons recapitulates these behavioral alterations. Transcriptomic profiling reveals that dFic depletion does not induce a canonical unfolded protein response, pointing to a specific post-transcriptional alteration rather than global ER stress. At the molecular level, dysregulated dFic alters the localization and abundance of Dop1R1. Finally, we demonstrate that this regulatory axis is evolutionarily conserved, as loss of FICD similarly diminishes motivated behaviors in C. elegans and mice. Together, these findings implicate FICD in the generation of motivated behavior and link dynamic control of ER proteostasis to dopamine-receptor maturation.

neuroscience↗

bioRxiv2024

Long-term hybridization in a karst window reveals the genetic basis of eye loss in cavefish

Eye loss is a hallmark trait of animals inhabiting perpetual darkness, yet the precise genetic variants underlying this evolutionary change remain largely unknown. The Mexican tetra (Astyanax mexicanus) provides a powerful model for dissecting the genetic basis of eye degeneration, as sighted surface fish and multiple independently evolved blind cave populations remain interfertile; yet despite decades of research and numerous QTL studies, the genetic basis of eye loss has remained unresolved at the level of specific variants. Here, we exploit a rare natural experiment in the Caballo Moro cave, where the collapse of a karst window created a partially illuminated pool inhabited by both fully eyed and completely eyeless cavefish of closely related genetic background. Whole-genome sequencing reveals a long-standing hybrid population between cave and surface lineages, enabling a dramatic refinement of the genetic architecture of eye degeneration to 203 candidate SNPs across 41 genes. Among these, we identified a nonsynonymous mutation in the lens gap-junction protein Connexin-50 (Cx50). CRISPR-based disruption of cx50 induces early eye loss in surface fish, and F2 laboratory crosses confirm genetic linkage between cx50 variants and eye size. Additional Cx50 mutations are present in independent cavefish populations and correlate with reduced eye size. Notably, variants in conserved regions of Cx50 also occur in other cave-dwelling fish and subterranean mammals, suggesting repeated evolutionary targeting of this gene. Introduction of the Caballo Moro mutation into mice causes cataracts and reduced eye and lens size, confirming its functional impact. Together, these findings identify the first SNP directly implicated in cavefish eye loss, demonstrate the power of natural hybrid populations to resolve the genetic basis of complex traits, and reveal Cx50 as a case of molecular convergence in vertebrate eye degeneration.

evolutionary biology↗

bioRxiv2023

Graded FGF activity patterns distinct cell types within the apical sensory organ of the sea anemone Nematostella vectensis

Bilaterian animals have evolved complex sensory organs comprised of distinct cell types that function coordinately to sense the environment. Each sensory unit has a defined architecture built from component cell types, including sensory cells, non-sensory support cells, and dedicated sensory neurons. Whether this characteristic cellular composition is present in the sensory organs of non-bilaterian animals is unknown. Here, we interrogate the cell type composition and gene regulatory networks controlling development of the larval apical sensory organ in the sea anemone Nematostella vectensis. Using single cell RNA sequencing and imaging approaches, we reveal two unique cell types in the Nematostella apical sensory organ, GABAergic sensory cells and a putative non-sensory support cell population. Further, we identify the paired-like (PRD) homeodomain gene prd146 as a specific sensory cell marker and show that Prd146+ sensory cells become post-mitotic after gastrulation. Genetic loss of function approaches show that Prd146 is essential for apical sensory organ development. Using a candidate gene knockdown approach, we place prd146 downstream of FGF signaling in the apical sensory organ gene regulatory network. Further, we demonstrate that an aboral FGF activity gradient coordinately regulates the specification of both sensory and support cells. Collectively, these experiments define the genetic basis for apical sensory organ development in a non-bilaterian animal and reveal an unanticipated degree of complexity in a prototypic sensory structure.

developmental biology↗

bioRxiv2023

Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

genomics↗

bioRxiv2022

Behavioral dissection of hunger states in Drosophila

Hunger is a motivational drive that promotes feeding, and it can be generated by the physiological need to consume nutrients as well as the hedonic properties of food. Brain circuits and mechanisms that regulate feeding have been described, but which of these contribute to the generation of motive forces that drive feeding is unclear. Here, we describe our first efforts at behaviorally and neuronally distinguishing hedonic from homeostatic hunger states in Drosophila melanogaster and propose that this system can be used as a model to dissect the molecular mechanisms that underlie feeding motivation. We visually identify and quantify behaviors exhibited by hungry flies and find that increased feeding duration is a behavioral signature of hedonic feeding motivation. Using a genetically-encoded marker of neuronal activity, we find that the mushroom body (MB) lobes are activated by hedonic food environments, and we use optogenetic inhibition to implicate a dopaminergic neuron cluster (PAM) to /{beta} MB circuit in hedonic feeding motivation. The identification of discrete hunger states in flies and the development of behavioral assays to measure them offers a framework to begin dissecting the molecular and circuit mechanisms that generate motivational states in the brain.

animal behavior and cognition↗

bioRxiv2022

Encoding of hunger by the neuronal epigenome slows aging in Drosophila

Hunger is, by necessity, an ancient motivational drive, yet the molecular nature of homeostatic pressures of this sort and how they modulate health and physiology are largely unknown. Here we show that the molecular encoding of hunger slows aging in Drosophila. We identify the branched-chain amino acids (BCAAs) as dietary hunger signals that extend lifespan despite increasing food intake when reduced, and in parallel show that optogenetic activation of a subset of hunger-promoting neurons is sufficient to recapitulate these effects. We find that remodeling of the neuronal histone acetylome is associated with dietary BCAA reduction, and that this requires BCAA metabolism in specific subsets of neurons. Preventing the histone acetylome from being molded by dietary BCAAs abrogates both increased feeding and extended lifespan. However, the mechanisms that promote feeding and modulate aging downstream of alterations in histone acetylation occur through spatially and temporally distinct responses; differential usage of the histone variant H3.3A in the brain is an acute response to hunger that promotes increased feeding without modulating lifespan, while a prolonged experience of hunger may slow aging by promoting a beneficial decrease of a set-point around which hunger levels are regulated. Identification of a molecular basis for the encoding of hunger and demonstration of its sufficiency in extending lifespan reveals that motivational states alone are deterministic drivers of aging and behavior.

physiology↗

bioRxiv2021

Strict adherence to Mendel's First Law across a large sample of human sperm genomes

Mendels Law of Segregation states that the offspring of a diploid, heterozygous parent will inherit either allele with equal probability. While the vast majority of loci adhere to this rule, research in model and non-model organisms has uncovered numerous exceptions whereby "selfish" alleles are disproportionately transmitted to the next generation. Evidence of such "transmission distortion" (TD) in humans remains equivocal in part because scans of human pedigrees have been under-powered to detect small effects. Recently published single-cell sequencing data from individual human sperm (n = 41,189; 969-3,377 cells from each of 25 donors) offer an opportunity to revisit this question with unprecedented statistical power, but require new methods tailored to extremely low-coverage data ([~]0.01 x per cell). To this end, we developed a method, named rhapsodi, that leverages sparse gamete genotype data to phase the diploid genomes of the donor individuals, impute missing gamete genotypes, and discover meiotic recombination breakpoints, benchmarking its performance across a wide range of study designs. After applying rhapsodi to the sperm sequencing data, we then scanned the gametes for evidence of TD. Our results exhibited close concordance with binomial expectations under balanced transmission, in contrast to tenuous signals of TD that were previously reported in pedigree-based studies. Together, our work excludes the existence of even weak TD in this sample, while offering a powerful quantitative framework for testing this and related hypotheses in other cohorts and study systems.

genomics↗

bioRxiv2020

Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice

It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan in Drosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.

genetics↗