Biology subjects

Riddle, M.

Publications and source records attributed to Riddle, M..

7 recordsLinked to original sources

bioRxiv2025

Adaptive Disruption of Carotenoid Metabolism in Cavefish via Loss of Beta-carotene oxygenase 2a (Bco2a)

Vitamin A is an essential micronutrient that supports vision, immunity, and development, yet excess vitamin A can be toxic1,2. Most vertebrates maintain tightly regulated vitamin A levels by cleaving dietary carotenoids into retinoids via specialized enzymes, including the mitochondrial carotenoid oxygenase Bco23,4. To what extent genetic changes in carotenoid-metabolism enzymes like Bco2 drive natural variation in vitamin A homeostasis remains unclear. Here we show that multiple cave-adapted populations of the Mexican tetra (Astyanax mexicanus) have evolved loss-of-function mutations in bco2a, leading to impaired carotenoid cleavage and dramatic carotenoid and vitamin A accumulation. These mutations yield enzymatically inactive Bco2a proteins, are under selection in cavefish, and may provide a physiological advantage under inconsistent carotenoid supply. Contrary to expectations from mammalian models where Bco2 loss induces oxidative damage5,6, cavefish appear to tolerate and even benefit from carotenoid accumulation, potentially through enhanced antioxidant capacity and modified mitochondrial metabolism. Our findings reveal that the vitamin A regulatory system is evolutionarily flexible, and that the adaptive loss of Bco2a function may enable survival in nutrient-variable, low-oxygen cave environments. This work provides a framework for understanding how animals balance essential nutrient thresholds in extreme environments.

evolutionary biology↗

bioRxiv2025

Enteric neural crest development in Astyanax mexicanus surface fish and cavefish

The enteric nervous system (ENS) regulates gastrointestinal (GI) functions such as secretion, blood flow, and motility, yet how its structure and function evolve with dietary adaptations remains unclear. Astyanax mexicanus, a teleost fish with surface and cave morphotypes, offers a model to explore these changes; cavefish exhibit altered GI motility and transit that may help them adapt to their unique diet. We compared early ENS development in surface fish and cavefish, tracking enteric neural crest cell (ENCC) migration and differentiation using phox2bb and HuC/D markers. We found that ENCCs reach the gut by 36 hours post-fertilization (hpf) in both morphotypes but migrate and differentiate more rapidly along the gut tube in cavefish. To explore the genetic basis of this difference, we used available genomic datasets to compare the predicted peptide sequences of genes important for ENS development in other species and identified mutations that could impact protein function, for example in the endothelin signaling genes important for ENCC migration and differentiation. We specifically examined the expression of endothelin-3 (edn3) and endothelin receptor-b (ednrb) during ENCC migration and found that the localization of edn3, but not ednrb, is consistent with a role in ENS development. Overall, our findings position A. mexicanus as a model for studying evolution of ENS development.

developmental biology↗

bioRxiv2024

Differential expression of sex regulatory genes in gonads of Astyanax mexicanus surface fish and cavefish

BackgroundAstyanax mexicanus is a single species of fish that consists of river-dwelling (surface) and cave-dwelling morphotypes. Little is known about how sexual determination, differentiation or reproduction have evolved in the surface morphs or cavefish, though divergence in reproductive strategy is expected as the latter have adapted to the novel cave environment. Evolution of the gonad transcriptome may underlie the differences in gamete morphology, fertility, and fecundity previously reported between morphotypes. ResultsWe compared the ovary and testis transcriptome of surface fish and cavefish at juvenile and adult stages. We found that samples clustered by developmental stage, sex, and morphotype identity. Several key genes that are typically associated with the female gonad in other vertebrates showed a reversal in sexual dimorphism or were not differentially expressed between sexes in A. mexicanus. In contrast, while gene expression typically associated with male gonads was largely conserved and consistent with vertebrate testicular expression profiles. Transcriptional and physiological differences between surface fish and cavefish morphotypes were observed in gonads from both sexes. Cavefish ovaries exhibited unique upregulation of neuron development and differentiation genes, and extensive innervation of the ovarian epithelium, while cavefish testes showed increased expression of angiogenesis regulating genes, and greater vasculature density compared to surface fish testes. ConclusionsThese results reveal significant gene expression differences between A. mexicanus surface fish and cavefish morphotypes that may have functional consequences in gonad morphogenesis and fertility. Our findings provide a foundation for investigating the evolution of sex regulatory pathways and reproductive strategies in animals adapting to new and challenging environments in which nutrient availability, temperature, and mate selection are suboptimal.

evolutionary biology↗

bioRxiv2024

Fisetin extends lifespan in a murine model of recessive dystrophic epidermolysis bullosa

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare genodermatosis characterized clinically by extensive inflammation, cutaneous destruction, and fibrosis that demonstrates properties similar to rapid skin aging. As tissue ages, it accumulates cellular damage and exhaustion leading to a state of senescence. Cellular senescence is an aging or disease-related phenomenon of stable exit from the cell cycle that leads to an increased inflammatory phenotype. RDEB and other EB subsets of patients need an adjunct to or alternate therapy that addresses the issues of inflammation, pain, and pruritus. Fisetin is a safe, naturally occurring compound proven to be effective at sensitizing senescent cells to cell death and ameliorating senescence-associated inflammation. In this paper, we demonstrate fisetins ability to increase survival and reduce senescent cell burden in a hypomorphic mouse model of RDEB.

molecular biology↗

bioRxiv2022

Genetic mapping of craniofacial traits in the Mexican tetra reveals loci associated with bite differences between cave and surface fish

The Mexican tetra, Astyanax mexicanus, includes interfertile surface-dwelling and cave-dwelling morphs, enabling powerful studies aimed at uncovering genes involved in the evolution of cave-associated traits. Compared to surface fish, cavefish harbor several extreme traits within their skull, such as a protruding lower jaw, a wider gape, and an increase in tooth number. These features are highly variable between individual cavefish and even across different cavefish populations. To investigate these traits, we created a novel feeding behavior assay wherein bite impressions could be obtained. We determined that fish with an underbite leave larger bite impressions with an increase in the number of tooth marks. Capitalizing on the ability to produce hybrids from surface and cavefish crosses, we investigated genes underlying these segregating orofacial traits by performing Quantitative Trait Loci (QTL) analysis with F2 hybrids. We discovered significant QTL for bite (underbite vs. overbite) that mapped to a single region of the Astyanax genome. This work highlights cavefish as a valuable genetic model for orofacial patterning and will provide insight into the genetic regulators of jaw and tooth development.

evolutionary biology↗

bioRxiv2021

The genetic basis of Drosophila melanogaster defense against Beauveria bassiana explored through evolve and resequence and quantitative trait locus mapping

Many of the molecular mechanisms for antifungal immunity in Drosophila melanogaster have been defined, but relatively little is known about the genetic basis for variation in antifungal immunity in natural populations. Using two population genetic approaches, Quantitative Trait Locus (QTL) Mapping and Evolve and Resequence (E&R), we explored the genetics underlying D. melanogaster immune defense against infection with the fungus Beauveria bassiana. Immune defense was highly variable both in the recombinant inbred lines from the Drosophila Synthetic Population Resource used for our QTL Mapping and in the synthetic outbred populations used in our E&R study. Survivorship of infection improved dramatically over just 10 generations in the E&R study, and continued to increase for an additional 9 generations, revealing a trade-off with uninfected longevity. Populations selected for increased defense against B. bassiana evolved cross resistance to a second, distinct B. bassiana strain but not to bacterial pathogens. The QTL mapping study revealed that sexual dimorphism in defense depends on host genotype, and the E&R study indicated that dimorphism also depends on the specific pathogen to which the host is exposed. Both the QTL Mapping and E&R experiments generated lists of potentially causal candidate genes, although these lists were non-overlapping.

genomics↗

bioRxiv2017

Insulin resistance in cavefish as an adaptation to a nutrient-limited environment

Periodic food shortage is one of the biggest challenges organisms face in natural habitats. How animals cope with nutrient limited conditions is an active area of study, of particular relevance in the context of the current increasing destabilization of global climate. Caves represent an extreme setting where animals have adapted to nutrient-limited conditions, as most cave environments lack a primary energy source. Here we show that cave-adapted populations of the Mexican Tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin resistant compared to the river-adapted population. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro. Surface/cave hybrid fish carrying the allele weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation similarly have increased body weight and insulin resistance. Higher bodyweight may be advantageous in the cave as a strategy to cope with infrequent food. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and dramatically reduced life-span. However, cavefish have a similar lifespan to surface fish (of greater than fourteen years) and do not accumulate advanced glycated end products (AGEs) in the blood that are typically associated with progression of diabetes-associated pathologies. Our findings raise the intriguing hypothesis that cavefish have acquired compensatory mechanisms that allow them to circumvent the typical negative effects associated with failure to regulate blood glucose.

evolutionary biology↗