Biology subjects

Lopes, A.

Publications and source records attributed to Lopes, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Post-outbreak surveillance reveals contrasting circulation dynamics of West Nile, Usutu and Bagaza viruses in southern Portugal, 2021 - 2023

Mosquito-borne orthoflaviviruses pose a significant threat to human and animal health worldwide. In Europe, West Nile (WNV), Usutu (USUV) and Bagaza (BAGV) viruses have expanded their geographic distribution and are detected with increasing frequency. Following the emergence of BAGV in 2021, we investigated the circulation dynamics and genomic diversity of orthoflaviviruses in southern Portugal, where their epidemiology remains poorly understood. Active Orthoflavivirus surveillance was conducted in birds and mosquitoes during 2021-2023 using serological and molecular assays, complemented by viral genome sequencing and phylogenomic analyses. Viral RNA was detected in 3.5% (41/1,171) of birds, while seroneutralization assays identified an overall seroprevalence of 55.3% (503/910). WNV RNA (lineage-1, strains WMed-1.2 and WMed-1.3) was detected annually in resident birds, including Alectoris rufa, Cyanopica cooki and Garrulus glandarius (1.5%, 18/1,171), and in Culex univittatus mosquitoes (0.8%, 2/255). Together with a WNV-specific seroprevalence of 28.5% (259/910) in birds, these findings support sustained local circulation. USUV RNA (Africa 3.1 sub-lineage) was detected in A. rufa in 2021 and 2023 (0.2%, 2/1,171), but seroprevalence was low (1.3%, 8/623), consistent with intermittent circulation. BAGV RNA (genotype-2) was detected only during the 2021 outbreak in A. rufa and Emberiza calandra (1.8%, 21/1,171), although BAGV-specific antibodies (6.6%, 60/910) were detected for up to two years after the outbreak, suggesting continued exposure or low-level circulation. Overall, our findings reveal contrasting circulation dynamics of orthoflaviviruses in southern Portugal. Sustained WNV circulation implies the need to strengthen avian and human surveillance in Portugal to better assess its public health risk, while the sporadic detection of USUV and BAGV underscores the value of long-term, integrated One Health surveillance for improving early warning and preparedness for emerging mosquito-borne diseases.

genetics↗

bioRxiv2026

CCR4+low-density neutrophils define a novel immunosuppressive subset associated with breast cancer progression and early mortality

Neutrophils are increasingly recognized as key players in cancer progression, yet their functional heterogeneity limits their therapeutic exploitation. In breast cancer (BC), elevated circulating and tumor-associated neutrophils have been associated with poor prognosis, and low-density neutrophils (LDN), particularly, have been linked to immunosuppression. However, the specific neutrophil subsets driving these effects remain undefined. Here, we identify a previously unrecognized CCR4-expressing neutrophil subset, strongly enriched among LDN, whose frequency rises with disease stage and correlates with faster progression and shorter survival. Serial blood sampling further showed that CCR4+LDN levels fluctuate in line with clinical course, with increases indicating near-term risk in metastatic patients. Our findings also reveal that this subset has an immunosuppressive signature more pronounced than that of the remaining LDN, migrates preferentially toward tumor-derived chemokines, and dampens T cell-driven tumor killing even when PD-1 is blocked. Additionally, in a pilot cohort of Triple-Negative BC patients on anti-PD-1 therapy, early changes in this population were associated with treatment outcome. Together, these results reveal a distinct neutrophil population that actively contributes to immune escape and tumor progression, establishing CCR4+LDN as a minimally invasive real-time biomarker of disease course and treatment response, and as a promising target for neutrophil-directed therapies in BC.

immunology↗

bioRxiv2026

SpaceBio Knowledge Hub: A LiteratOmics Platform for Microgravity and Space Biology Research

Space biology literature is growing exponentially. Existing infrastructure has not kept pace with organizing, synthesizing, and disseminating this knowledge. We present SpaceBio SpaceBio Knowledge Hub (www.spacebio.space), an integrated digital ecosystem that combines artificial intelligence, real-time data integration, and open-access infrastructure to advance research, education, and collaboration in microgravity, space biology and space exploration. The platform applies AI-driven approaches including natural language processing, machine learning, and automated content generation to construct a semantic atlas of the field. The atlas reveals the hierarchical thematic organization underlying microgravity-induced biological responses, space mission infrastructure, planetary science, and astrobiology. As part of this effort, SpaceBio is moving toward the construction of a LiteratOmics framework for microgravity, and space biology a systematic, AI-enabled approach to mining, integrating, and structuring the primary literature generated by omics-driven spaceflight research, treating the scientific literature itself as a navigable data layer alongside genomic, transcriptomic, and proteomic datasets. Built on a scalable, cloud-based architecture with a user-centered interface, SpaceBio supports literature exploration, data integration, and knowledge discovery for researchers, educators, students, industry partners, and citizen scientists. The platform also functions as a community-building ecosystem. It integrates hands-on research initiatives, AI-generated educational content, pilot data science projects, and social responsibility programs that broaden participation without compromising scientific rigor. AI-enabled digital environments can transform fragmented literature into a navigable knowledge landscape. SpaceBio accelerates research productivity, strengthens STEM education, and supports the global space life sciences community as human space exploration enters in the most ambitious era.

scientific communication and education↗

bioRxiv2026

Epigenetic signatures of infection within and across generations in the endangered Loggerhead sea turtle

Infection can substantially reduce host fitness and influence population dynamics, yet it is often difficult to detect and quantify in wild animal populations. Molecular tools offer a valuable means of identifying cryptic infection in natural systems. Using whole-genome bisulfite sequencing, we examined whether infection with the parasitic leech Ozobranchus margoi is associated with DNA methylation variation in loggerhead sea turtles (Caretta caretta), while also assessing the potential value of this variation as a biomarker of parasite infection. In nesting females, we identified infection-associated differentially methylated CpG sites associated with genes implicated in immune signalling and cellular regulation. Offspring of infected females also showed infection-associated methylation patterns, despite not being directly exposed to the parasite themselves. Differential methylation analyses identified genes involved in immunity, neurodevelopment and metabolic activity, with limited overlap in associated genes and no overlap in differentially methylated sites between generations. Maternal and offspring genome-wide methylation levels showed a non-linear association that differed subtly with maternal infection status, indicating that infection modifies intergenerational methylation associations. Finally, methylation profiles showed strong discriminatory power for maternal infection status in both maternal and hatchling samples using machine learning models, supporting their potential as candidate biomarkers of cryptic infection. Together, these results show that parasite infection is associated with distinct, generation-specific DNA methylation signatures, and highlight the potential value of epigenetic data for monitoring cryptic infection states in conservation-relevant systems.

genetics↗

bioRxiv2026

Kinetics of Hypoglycemia in Diabetes Patients Informs Development of New Modes of Glucagon Therapy

Insulin therapy revolutionized the care of patients with diabetes starting [~]100 years ago, yet insulin-induced hypoglycemia remains a serious life-threatening complication of insulin therapy. Glucagon is a highly effective treatment; however current dosage forms remain under-utilized due to poor patient compliance. The development of improved and situation-specific glucagon therapies remains challenging due to the poor drug stability and incomplete knowledge of the kinetics of different hypoglycemic events. Thus, we analyzed continuous glucose monitor (CGM) data from 1135 patients with type 1 diabetes (T1D) representing 246.18 patient years. We show that a surprisingly large proportion of hypoglycemic episodes (20-30%) are follow-on events resulting from under-treatment of prior events, and that the average duration of independent hypoglycemic events can last up to 79 to 108 minutes. We further show that the kinetics of hypoglycemic onset and persistence varies significantly by patient history, severity, time of occurrence. Guided by these findings, we recognize the opportunity to develop high-density, readily-soluble, and thermostable (ReST) solid glucagon formulations, and painless application-specific microneedle-patches that are in line with the timing needs of T1D patients who are awake and asleep. Thus, we demonstrate (1) on-demand patches for rapid prevention or treatment of mild hypoglycemia during the day, and (2) enzyme-driven hypoglycemia-responsive patches supporting autonomous glucagon release during the night. We show excellent in vitro glucagon stability, loading, and release kinetics of both systems and demonstrate their ability to treat hypoglycemia in diabetic animals. The engineering of these delivery systems demonstrates the potential of human CGM data and solid glucagon formulations to enable new modes of glucagon therapy, thereby expanding the clinical role of glucagon beyond the emergency setting.

bioengineering↗

bioRxiv2026

Warming-induced sex bias fuels deceptive conservation success in sea turtles

Global warming threatens species with temperature-dependent sex determination (TSD) by risking extreme offspring sex-ratio bias. In sea turtles, warmer incubation conditions produce more females. Such biases can transiently inflate apparent population growth before male scarcity undermines reproduction, possibly leading to population extinction. Here, we combine 15 years of field monitoring, drone-based sex-ratio surveys, Argos telemetry, and eco-physiological modelling to test whether rising temperatures underpin the rapid increase in loggerhead (Caretta caretta) nesting in Cabo Verde, one of the worlds largest populations. Historical air temperature, lagged by one generation, predicts current nest counts, consistent with a climate-driven, female-biased population. Drone surveys reveal an approximately 9:1 female-to-male breeding sex ratio across two consecutive breeding seasons, and simulations reproduce observed nesting trajectories under historical warming but not under null (no-warming) scenarios. Extending the analysis to 28 global loggerhead populations reveals consistent links between temperatures, latitude, and nesting trends. Our results identify warming-induced sex ratio bias as a key, yet deceptive, driver of apparent recovery, highlighting the need to reassess conservation success through the lens of demography of TSD species.

ecology↗

bioRxiv2026

DNA methylation reveals evolved buffering responses to climate-driven sex ratio skew in sea turtles

Species with temperature-dependent sex determination (TSD), including all sea turtles which produce females at warmer temperatures, face projections of demographic collapse under climate-driven sex ratio skews. However, the accuracy of such predictions remains uncertain, as current models rely heavily on indirect sex ratio proxies due to the lack of a scalable, non-invasive method for sexing hatchlings. Through whole methylome sequencing, we identified 777 sex-associated DNA methylation markers from blood samples of sex-verified loggerhead turtle (Caretta caretta) hatchlings incubated at three controlled temperatures. Applying these markers to a large-scale field experiment showed that classic nest temperature-based models overestimated female production by an average of up to 60.2%, suggesting the presence of evolved buffering mechanisms against thermal effects on sex determination. Our findings highlight the need to revise climate-driven sex ratio forecasts with empirical field data, such as methylation-based assessments, to better understand and safeguard the hidden resilience of vulnerable TSD species.

zoology↗

bioRxiv2025

A single-cell transcriptomic atlas maps cerebellar astrocyte diversity and uncovers the transcriptional code underlying their maturation trajectories

Astrocytes are increasingly recognized as key regulators of neural circuit development and function, with mounting evidence revealing substantial heterogeneity within and across brain regions. Yet, the full extent of this diversity and its developmental mechanisms remain poorly understood. To address this, we leveraged the uniqueness of the mouse cerebellum, which hosts well-defined astrocyte types and established progenitor pools. Through complementary multi-modal omic approaches, including single-cell RNA sequencing, spatial transcriptomics, trajectory inference, clonal lineage reconstruction, and gene expression and regulatory network analyses, we systematically dissected the molecular diversity and ontogenesis of cerebellar astrocytes. We identified known types and uncovered new subtypes with functional specialization, inferring their developmental trajectories from multiple embryonic niches and postnatal progenitor sources with fate divergence, convergence, and restriction. We further predicted a hierarchical transcriptional regulator code governing this diversification, operating at multiple levels: distinct regulatory modules i) reflect embryonic regionalization and lineage; ii) determine broad astroglial identity; specify iii) Bergmann versus non-Bergmann fates; and guide iv) astrocyte type and v) subtype acquisition. Our findings map and temporally organize transcriptional programs that capture key determinants of astrocyte fate, integrating them along defined trajectories toward diverse astrocyte identities. This high-resolution framework for cerebellar glial diversification offers a model to be challenged across other brain regions.

neuroscience↗

bioRxiv2025

Monolithic Shape-Shifting Absorbable Implants for Long-Term Contraception

Reversible contraceptives empower women to prevent unintended pregnancies and enable family planning. However, the need for frequent dosing with pills or injections often leads to suboptimal medication adherence and reduced effectiveness-an issue common to many chronic conditions. Long-acting drug delivery implants offer a compelling alternative by enabling autonomous, multi-year drug release, thereby improving real-world adherence and treatment outcomes. However, user acceptability and access are limited by need for invasive insertion and surgical end-of-life removal, particularly in low-resource settings, as well as by limited drug loading and suboptimal drug utilization efficiency, which constrain both the duration of therapy and the range of drugs that can be effectively delivered. To address these limitations, we developed the Monolithic Shape-shifting Absorbable Implants for Chronic Care (MoSAIC) platform-a minimally invasive, fully bioresorbable system that integrates compacted drug formulations with a space-efficient device architecture. This approach reduces implant size, eliminates the need for surgical removal, and prolongs therapeutic duration compared to existing implants. We develop compacted formulations of the contraceptive drug levonorgestrel (LNG), and other poorly water-solubility drugs, demonstrating exceptional drug loading (100% w/w) and multi-year sustained drug release via surface-mediated dissolution in rats. When incorporated into MoSAIC devices, these formulations enable high-efficiency drug loading and zero-order drug release kinetics with geometrically tunable rates and durations. As a result, MoSAIC systems can be designed to be smaller, less invasive, and/or longer lasting than current contraceptive implants such as Jadelle(R) and Nexplanon(R). The MoSAIC platform expands access to reversible contraception and supports long-term medication adherence, with the potential to improve health outcomes and quality of life. More broadly, it provides a flexible approach for delivering other potent, low-solubility therapeutics and lays the foundation for a "dose it and forget it" paradigm in chronic disease management, where adherence is designed into the therapy itself.

bioengineering↗

bioRxiv2025

Human jejunal enteroids for studies of epithelial drug transport and metabolism

Intestinal enteroids are stem cell-based "mini-guts" that mimic many aspects of the corresponding epithelial barrier in vivo. Here, we established and characterized differentiated apical-out (AO) and basal-out (BO) jejunal enteroids in suspension and followed their differentiation by quantitative global proteomics and different microscopic techniques. The barrier integrity and function and subcellular location of nutrient and clinically important drug transporters were investigated in the matured enteroids using live-cell microscopy. The presystemic metabolism of two drugs by CYP3A4 was determined and the results were used to predict the pharmacokinetics after oral administration by a PBPK population model. The differentiated AO enteroids displayed a protein profile that overlapped both qualitatively and quantitatively with that of freshly isolated jejunal enterocytes and tissue. They exhibited a morphology that recapitulates the mature villus enterocyte in vivo, formed an intact barrier with a well-developed glycocalyx and are impermeable to the hydrophilic low molecular weight compound lucifer yellow and transported a medium chain fatty acid derivative by FATP4 into lipid deposits. The clinically important ABC-transporters Pgp and BCRP were expressed at near in vivo levels, had the correct subcellular localization and effluxed their substrates. Terfenadine and midazolam were metabolized by CYP3A4 and the results were used to predict the clinical pharmacokinetics of the drugs after oral administration with good accuracy. We conclude that suspended 3D AO enteroids provide a physiologically relevant model for studies of intestinal function that offers convenient access to the apical surface and is easy to dispense in multi-wells formats for large scale experimentation.

cell biology↗

bioRxiv2024

Usutu virus African 3.1 lineage, Portugal, 2021-2023

BackgroundUsutu virus (Orthoflavivirus usutuense, USUV), a neurotropic arthropod-borne RNA virus of the family Flaviviridae, is a zoonotic virus that has spread throughout the European continent over the last three decades, since its emergence in Italy in 1996. However, no cases of USUV have been reported in Portugal so far. Material and methodsIn the scope of an active surveillance program for Orthoflavivirus, we collected growing feather samples from 249 red-legged partridges (Alectoris rufa) hunted in southern Portugal during the 2021-2023 hunting seasons. Samples positive for USUV were subjected to whole genome sequencing and strain characterization. ResultsTwo partridges tested positive for USUV. Phylogenetic analyses of whole and partial genomes assigned the USUV strains to the African 3 lineage, specifically the African 3.1 sub-lineage. ConclusionsOur study confirms, for the first time, the circulation of USUV in wild birds in Portugal. Active surveillance of hunted partridges proved to be a useful, accessible, and cost-effective method for USUV monitoring, further supporting their value as effective sentinels for Orthoflavivirus surveillance. Given the ongoing circulation of USUV and the increasing risk of its spillover to other domestic and wild animals, and humans, additional efforts are needed to improve virus surveillance in Portugal from a One Health perspective.

microbiology↗

bioRxiv2024

DE Novo emerged gene SEarch in Eukaryotes with DENSE

The discovery of de novo emerged genes, originating from previously noncoding DNA regions, challenges traditional views of species evolution. Indeed, the hypothesis of neutrally evolving sequences giving rise to functional proteins is highly unlikely. This conundrum has sparked numerous studies to quantify and characterize these genes, aiming to understand their functional roles and contributions to genome evolution. Yet, no fully automated pipeline for their identification is available. Therefore, we introduce DENSE (DE Novo emerged gene Search), an automated Nextflow pipeline based on two distinct steps: detection of Taxonomically Restricted Genes (TRGs) through phylostratigraphy, and filtering of TRGs for de novo emerged genes via genome comparisons and synteny search. DENSE is available as a user-friendly command-line tool, while the second step is accessible through a web server upon providing a list of TRGs. Highly flexible, DENSE provides various strategy and parameter combinations, enabling users to adapt to specific configurations or define their own strategy through a rational framework, facilitating protocol communication, and study interoperability. We apply DENSE to seven model organisms, exploring the impact of its strategies and parameters on de novo gene predictions. This thorough analysis across species with different evolutionary rates reveals useful metrics for users to define input datasets, identify favorable/unfavorable conditions for de novo gene detection, and control potential biases in genome annotations. Additionally, predictions made for the seven model organisms are compiled into a requestable database, that we hope will serve as a reference for de novo emerged gene lists generated with specific criteria combinations. Significance StatementThe identification and classification of de novo genes, which originate from noncoding regions of DNA, remain an ongoing challenge in genomics research. While various approaches have been employed for their identification, the lack of a standardized protocol has resulted in varying lists of de novo genes across studies. This study introduces a novel tool: DENSE, that formalizes the common practices used in the field into a comprehensive and automated pipeline. DENSE streamlines the identification of taxonomically restricted genes, homology searches, and synteny analysis. This standardized methodology aims to enhance the accuracy and reliability of de novo gene identification, fostering a deeper understanding of the evolutionary mechanisms that drive gene birth and shape the genetic diversity of organisms.

genomics↗

bioRxiv2024

Loss of NAT10 disrupts enhancer organization via p300 mislocalization and suppresses transcription of genes necessary for metastasis progression.

Acetylation of protein and RNA represent a critical event for development and cancer progression. NAT10 is the only known RNA acetylase that catalyzes the N4-actylcytidine (ac4C) modification of RNAs. Here, we show that the loss of NAT10 significantly decreases lung metastasis in allograft and genetically engineered mouse models of breast cancer. NAT10 interacts with a mechanosensitive, metastasis susceptibility protein complex at the nuclear pore. In addition to its canonical role in RNA acetylation, we find that NAT10 interacts with p300 at gene enhancers. NAT10 loss is associated with p300 mislocalization into heterochromatin regions. NAT10 depletion disrupts enhancer organization, leading to alteration of gene transcription necessary for metastatic progression, including reduced myeloid cell-recruiting chemokines that results in a less metastasis-prone tumor microenvironment. Our study uncovers a distinct role of NAT10 in enhancer organization of metastatic tumor cells and suggests its involvement in the tumor-immune crosstalk dictating metastatic outcomes.

cancer biology↗

bioRxiv2023

DNA methylation carries signatures of sublethal effects under thermal stress in loggerhead sea turtles

Rising global temperatures are a major threat to biodiversity. Whilst research generally focuses on thermal tolerance and mortality, sublethal effects may alter population dynamics and subsequently the adaptive potential of species. However, detecting such effects in the wild can be challenging, particularly for endangered and long-lived species with cryptic life histories. This necessitates the development of molecular tools to identify their signatures. In a split-clutch design experiment, we relocated clutches of wild, nesting loggerhead sea turtles (Caretta caretta) to a protected, in-situ hatchery. Eggs were then split into two sub-clutches incubated under shallow (35cm) or deep (55cm) conditions, with those in the shallow treatment experiencing significantly higher temperatures. Whilst no difference in hatching success was observed between treatments, hatchlings that emerged from the shallow, warmer treatment had altered length-mass relationships, and were weaker at fitness tests of locomotion capacity than their siblings incubated in the deep, cooler treatment. To characterise the molecular signatures of these thermal effects, we performed whole genome bisulfite sequencing on blood samples collected upon emergence. This identified 714 differentially methylated sites between treatments, including on genes with neuronal development, cytoskeleton, and sex determination functions. Taken together, our results show that higher incubation temperatures can induce sublethal effects in hatchlings, which are reflected in their DNA methylation status at identified sites. Such sites could be used as biomarkers of thermal stress, especially if they are retained across life stages. Overall, this study suggests that global warming may have population-level consequences for loggerhead sea turtles, by reducing hatchling quality, dispersal capacity and the adaptive potential of this species. Conservation efforts for climate-threatened taxa like endangered sea turtles will therefore benefit from strategies that monitor and mitigate exposure to incubation temperatures that lead to sublethal effects.

genomics↗

bioRxiv2023

Productive foraging sites enhance maternal health and impact offspring fitness in a capital breeding species

Feeding ecology is an essential component of an organisms life, but foraging comes with risks and energetic costs. Species in which populations exhibit more than one feeding strategy, such as sea turtles, are good systems for investigating how feeding ecology impacts life-history traits, reproduction and carried over effects across generations. Here, we investigated how the feeding ecology of loggerhead sea turtles (Caretta caretta) nesting at the Cabo Verde archipelago correlates with reproductive outputs and offspring fitness. We determined the feeding ecology of female turtles before and during the breeding season from stable isotope analysis of carbon and nitrogen, and correlated isotopic ratio with female and hatchling fitness traits. We found that female turtles feeding at higher trophic positions produced larger clutches. We also found that females with less depleted {delta}13C values, typical of productive foraging areas, had greater fat reserves, were less likely to be infected by leech parasites, and produced heavier offspring. The offspring of infected mothers with less depleted {delta}13C values performed best in crawling and self-righting trials than those of non-infected mothers with less depleted {delta}13C values. Overall, our study shows adult female loggerheads that exploit productive areas build capital reserves that impact their reproductive success and offspring fitness. Together, we uphold the suggestion that not all foraging habitats are equal, and can alter the fitness of populations.

ecology↗

bioRxiv2023

Regional Differences in Progenitor Consumption Dynamics Shape Brain Growth during Development

Developing mammalian brains are characterized by disproportionate growth of the forebrain compared to other regions. How this localized expansion occurs is, however, largely unknown. To address this, we identified region-specific neurogenic patterns by creating a single-cell-resolution birthdate atlas of the mouse brain (https://www.neurobirth.org). We report that in forebrain regions, neurogenesis is sustained compared to the hindbrain, where neurogenesis is transient and limited to early brain development. Sustained forebrain neurogenesis reflects lengthened cell cycle and reduced consumptive divisions of ventricular zone progenitors, resulting in a preserved germinal cell pool. Using single-cell RNA sequencing, we identify functional molecular programs of ventricular zone progenitors that spatially and temporally regulate progenitor cycling properties, including through loss-of-function of the forebrain-enriched mitochondrial membrane protein Fam210b. These results reveal a parsimonious mechanism to locally regulate neuronal production, in which the time window during which progenitors generate cells is a critical determinant of region-specific brain expansion.

neuroscience↗

bioRxiv2023

Shifting KRAS hotspot mutations inhibition paradigm in colorectal cancer

KRAS hotspot mutations are difficult to target, highlighting the need of developing new specific target drugs for cancers driven by these mutations, like colorectal cancer (CRC). Here, we discover a new ruthenium compound, PMC79, that inhibits specifically mutated KRAS and the downstream signaling ERK and AKT proteins both "in vitro" and "in vivo". We demonstrated that PMC79 inhibits KRAS mutated kinase activity and is selective for KRAS mutations not affecting the KRAS wild-type protein. KRAS inhibition is not dependent on actin polymerization or on proteasome. Molecular docking analysis suggests that this effect might result from protein dynamics associated with the mutations. We demonstrated that low doses of PMC79 potentiate 5-fluorouracil anticancer effect. "In vivo" PMC79 "proof of concept" showed that it reduces tumor growth in the CAM-xenograft model and induces necrosis of the tumor in the xenograft mice model. PMC79 is a promising new "magic bullet" for CRCs harboring mutated KRAS.

pharmacology and toxicology↗

bioRxiv2023

Tgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape

The hindlimb and external genitalia of present-day tetrapods are thought to derive from an ancestral common primordium that evolved to generate a wide diversity of structures adapted for efficient locomotion and mating in the ecological niche conquered by the species. We show that despite long evolutionary distance from the ancestral condition, the early primordium of the mouse external genitalia preserved the capacity to take hindlimb fates. In the absence of Tgfbr1, the pericloacal mesoderm generates an extra pair of hindlimbs at the expense of the external genitalia. It has been shown that the hindlimb and the genital primordia share many of their key regulatory factors. Tgfbr1 controls the response to those factors by modulating the accessibility status of regulatory elements that control the gene regulatory networks leading to the formation of genital or hindlimb structures. Our work uncovers a remarkable tissue plasticity with potential implications in the evolution of the hindlimb/genital area of tetrapods, and identifies a novel mechanism for Tgfbr1 activity that might also contribute to the control of other physiological or pathological processes.

developmental biology↗