Biology subjects

Davis, M. C.

Publications and source records attributed to Davis, M. C..

4 recordsLinked to original sources

bioRxiv2026

Ancient origin of the dorso-ventral patterning system of vertebrate paired fins

The origin of paired fins was a major event in early vertebrate history that fuelled the adaptive radiation of the gnathostome clade. Evidence for the conservation of ancient regulatory systems between paired and median fins supports a model in which appendage-patterning mechanisms first evolved in the midline and were later redeployed to a new embryonic context, the flank. However, while paired fins and limbs are asymmetric along the dorso-ventral (DV) axis, the equivalent axis does not exist in median fins, which are symmetric across the midline, raising questions of how DV patterning evolved. Here, we combine genetic tools in zebrafish with comparative expression analyses in representative ray-finned and cartilaginous fishes to show that a subset of limb dorsoventral (DV) patterning genes are expressed during median fin development. Using genetic lineage tracing of the canonical limb dorsalizing factor lmx1bb, we further demonstrate that, although lmx1bb-derived cells occupy distinct spatial domains across fin types, a subset of this lineage is fated to differentiate into fin-ray osteoblasts in both paired and median fins. To test the potential conservation of regulatory modules across fin types, we generated a series of deletion mutants for two known lmx1b mouse limb enhancers, LARM1 and LARM2, that we show are partially conserved upstream of zebrafish lmx1bb. These experiments revealed that LARM function is essential for dorsoventral patterning in the paired pectoral and pelvic fins of zebrafish but is dispensable for formation of the unpaired dorsal and anal fins. To determine if the paired fin specificity of LARM-mediated lmx1b regulation is a feature of more basal gnathostomes, we used a single cell multiomics (RNAseq + ATACseq) approach in the epaulette shark Hemiscyllium ocellatum, a representative chondrichthyan and outgroup to osteichthyans. Strikingly, these analyses demonstrated linkages between the LARM1 enhancer and lmx1b in the unpaired dorsal fins of epaulette sharks, as well as the deployment of a Lmx1b-mediated regulatory network whose core downstream components are conserved between dorsal fins, paired fins, and limbs. Collectively, these data support the ancient origin of a "DV" regulatory module in median fins that was redeployed during the early evolution paired fins, facilitating the assembly of the DV patterning axis. Intriguingly, multiome-based inference of global fin network architecture in epaulette shark also revealed reduced regulatory complexity in pectoral relative to median fins, suggesting that co-option as a mechanism for anatomical innovation can proceed through selective streamlining of ancestral network components.

developmental biology↗

bioRxiv2025

Multiblock Integration and Modeling of Localized Microbiome, Metabolome, and Clinical Metadata to Identify Biomarkers Predictive of Outcome in Veterans with Non-Healing Wounds

The chronic wound microenvironment consists of a complex milieu of host cells, microbial species, and metabolites. While much is known about wound microbiomes, our knowledge of metabolic landscapes influencing wound healing is limited. Furthermore, integrating complex datasets into predictive models of wound healing is almost non-existent. Microbial rRNA and total metabolites were extracted from 45 diabetic foot ulcers (DFU) debridement samples from 13 patients, with 25 from non-healing wounds and 20 from healing wounds that remained closed for over 30 days. 16S rRNA sequencing and global metabolomics were performed and clinical metadata collected. Healing outcome was modeled as a function of three blocks of features (N = 21 clinical, 634 microbiome, and 865 metabolome) using DIABLO (Data Integration Analysis for Biomarker Discovery using Latent Components). The final model selected 176 features (N = 15 clinical, 8 microbiome, and 153 metabolome) and the correct clinical outcome was predicted with an accuracy of nearly 94%. These results indicate that integrating multi-omics data with clinical metadata can predict clinical wound healing with low error rates. Furthermore, the biomarkers selected within the model offer novel insights into wound microenvironment composition which may reveal innovative therapeutic approaches and improve treatment efficacy in difficult-to-heal wounds.

systems biology↗

bioRxiv2020

The fragile X mental retardation protein promotes adjustments in cocaine self-administration that preserve reinforcement level

The fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cocaine-induced neuronal plasticity and is critical for the normal development of drug-induced locomotor sensitization, as well as reward-related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing an intravenous cocaine self-administration (IVSA) assay in Fmr1 knockout (KO) and wild type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose-response testing. Later, with access to the original acquisition dose under increasing schedules of reinforcement (FR1, FR3, FR5), Fmr1 KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, operant conditioning with a palatable food reinforcer does not show similar deficits, indicating that our results do not stem from broad learning or reward-related deficits in Fmr1 KO mice. Additionally, we find an FMRP target, the activity-regulated cytoskeleton-associated protein (Arc), to be significantly reduced in Fmr1 KO mouse synaptic fractions from the nucleus accumbens following cocaine IVSA. Overall, our findings suggest that FMRP facilitates adjustments in drug self-administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings in Arc KO mice, suggest Arc as a target of FMRP to investigate in behavioral shifts that occur when drug availability is altered.

neuroscience↗

bioRxiv2018

Deep evolutionary origin of limb and fin regeneration

Salamanders and lungfishes are the only sarcopterygians (lobe-finned vertebrates) capable of complete limb and paired fin regeneration, respectively. Among actinopterygians (ray-finned fishes), regeneration after amputation at the fin endoskeleton has only been demonstrated in Polypterid fishes (Cladistia). Whether complete appendage regeneration in sarcopterygians and actinopterygians evolved independently or has a common origin remains unknown. Here we combine fin regeneration assays and comparative RNA-seq analysis to provide support for a common origin of a paired appendage regeneration in osteichthyes (bony vertebrates). We show that, in addition to Polypterids, regeneration after fin endoskeleton amputation occurs in extant representatives of all major actinopterygian clades: the American paddlefish, (Chondrostei), the spotted gar (Holostei), as well as in two cichlid species, the white convict and the oscar (Teleostei). Our comparative RNA-seq analysis of regenerating blastemas of axolotl and Polypterus reveals the activation of common genetic pathways and expression profiles, consistent with a pan-osteichthyes genetic program of appendage regeneration. Collectively, our findings support a deep evolutionary origin of paired appendage regeneration in osteichthyes and provide an evolutionary framework for studies on the genetic basis of appendage regeneration.

evolutionary biology↗