Biology subjects

York, J.

Publications and source records attributed to York, J..

6 recordsLinked to original sources

bioRxiv2025

An Evolutionary Novelty in TRPV1 Functional Regulation: Characterization of a Dominant-Negative Isoform Exclusive to Catarrhine Primates

TRPV1, a member of the transient receptor potential (TRP) family, is a non-selective cation channel primarily known for its role in pain perception, inflammation, and thermosensation. In mammals, it responds to noxious heat (>43{degrees}C) and chemical stimuli such as capsaicin and protons. It is widely expressed in sensory neurons, notably in the dorsal root and trigeminal ganglia. However, it is also found in some non-neuronal tissues, like the skin and bladder. The human canonical variant of TRPV1 renders a protein with 839 residues. Different splice variants have been described, and some display a dominant negative effect, partially or totally inhibiting the activity of the canonical counterpart. Here, we characterize a splice variant that encodes for a channel of 850 amino acids (TRPV1850). This variant is an evolutionary novelty of catarrhine (Old World monkeys and apes) primates, incorporating an exon of 33 bp long. Both imaging of membrane expression and electrophysiological recordings suggest that TRPV1850 alone does not reach the plasma membrane. However, in cells co-expressing the canonical and TRPV1850 variants, the latter would act as a dominant negative, preventing the canonical variant from reaching the plasma membrane and rendering smaller macroscopic currents in response to capsaicin. Thus, this new isoform of the TRPV1 ion channel represents a novel form of functional regulation only present in apes and Old World monkeys. SignificanceWe identified a novel isoform of the TRPV1 ion channel, a protein essential for detecting pain and heat stimuli unique to apes and Old World monkeys. This isoform contains an additional exonic sequence encoding eleven amino acids, which originated in the common ancestor of apes and Old World monkeys. This additional exonic sequence disrupts a specific domain in the N-terminal region of the protein, resulting in functional differences. Unlike the canonical TRPV1 isoform, this variant cannot reach the plasma membrane independently. Instead, it exerts a dominant-negative effect by interfering with the canonical TRPV1 protein, reducing its ability to localize to the cell surface and diminishing its responsiveness to capsaicin, a well-known TRPV1 activator.

evolutionary biology↗

bioRxiv2025

Kruppel-like Factors Play Essential Roles in Regulating Pluripotency and the Formation of Neural Crest Stem Cells

The evolutionary transition from simple chordate body plans to complex vertebrate body plans was driven by the acquisition of the neural crest, a stem cell population that retains broad, multi-germ layer developmental potential long after most embryonic cells have become lineage restricted. We have previously shown that neural crest cells share significant gene regulatory architecture with pluripotent blastula stem cells. Here we examine the roles that Kruppel-like Family (Klf) transcription factors play in these stem cell populations. Although Klf4 has established roles in regulating pluripotency in mammalian stem cells cultures, we find that in Xenopus it is klf2 that is highly expressed in pluripotent blastula stem cells. klf2 expression is down-regulated as cells transition to a neural crest state while a related klf factor, klf17, is significantly up regulated in response to neural crest induction. We used gain and loss of function studies to compare the activities of these closely related factors and found that they have both shared and distinct activities. Inhibition of either klf2 or klf17 activity led to significantly expanded expression of pluripotency, neural plate border and neural crest factors in neurula stage embryos, leading us to hypothesize that klf factors regulate the exit from pluripotency and proper establishment of the boundary of the neural crest domain. To gain further insights into the role of klf factors in the evolution of the neural crest, we examined their expression in the jawless vertebrate, Petromyzon marinus (sea lamprey). We find that lamprey have a klf2/4 and a klf17 gene, but that only klf17 is expressed in blastula and neural crest stem cells. Moreover, ectopic expression of lamprey klf17 in Xenopus embryos phenocopies Xenopus klf17 activity. These data suggest that klf17, rather than klf4, may have been the ancestral klf factor that functioned in these GRNs in stem vertebrates.

developmental biology↗

bioRxiv2023

Shared features of blastula and neural crest stem cells evolved at the base of vertebrates

The neural crest is vertebrate-specific stem cell population that helped drive the origin and evolution of the vertebrate clade. A distinguishing feature of these stem cells is their multi-germ layer potential, which has drawn developmental and evolutionary parallels to another stem cell population--pluripotent embryonic stem cells (animal pole cells or ES cells) of the vertebrate blastula. Here, we investigate the evolutionary origins of neural crest potential by comparing neural crest and pluripotency gene regulatory networks (GRNs) in both jawed (Xenopus) and jawless (lamprey) vertebrates. Through comparative gene expression analysis and transcriptomics, we reveal an ancient evolutionary origin of shared regulatory factors between neural crest and pluripotency GRNs that dates back to the last common ancestor of extant vertebrates. Focusing on the key pluripotency factor pou5 (formerly oct4), we show that the lamprey genome encodes a pou5 ortholog that is expressed in animal pole cells, as in jawed vertebrates, but is absent from the neural crest. However, gain-of-function experiments show that both lamprey and Xenopus pou5 enhance neural crest formation, suggesting that pou5 was lost from the neural crest of jawless vertebrates. Finally, we show that pou5 is required for neural crest specification in jawed vertebrates and that it acquired novel neural crest-enhancing activity after evolving from an ancestral pou3-like clade that lacks this functionality. We propose that a pluripotency-neural crest GRN was assembled in stem vertebrates and that the multi-germ layer potential of the neural crest evolved by deploying this regulatory program.

evolutionary biology↗

bioRxiv2023

Evolution of sex differences in cooperation:the role of trade-offs with dispersal

AbstractExplaining the evolution of sex differences in cooperation remains a major challenge. Comparative studies highlight that offspring of the more philopatric sex tend to be more cooperative within their family groups than those of the more dispersive sex but we do not understand why. The leading Philopatry hypothesis proposes that the more philopatric sex cooperates more because their higher likelihood of natal breeding increases the direct fitness benefits of natal cooperation. However, the Dispersal trade-off hypothesis proposes that the more dispersive sex cooperates less because preparations for dispersal, such as extra-territorial prospecting, trade-off against natal cooperation. Here, we test both hypotheses in cooperatively breeding white-browed sparrow weavers (Plocepasser mahali), using a novel high-resolution automated radio-tracking method. First, we show that males are the more dispersive sex (a rare reversal of the typical avian sex-difference in dispersal) and that, consistent with the predictions of both hypotheses, females contribute substantially more than males to cooperative care while within the natal group. However, the Philopatry hypothesis cannot readily explain this female-biased cooperation, as females are not more likely than males to breed within their natal group. Instead, our radio-tracking findings support the Dispersal trade-off hypothesis: males conduct pre-dispersal extra-territorial prospecting forays at higher rates than females and prospecting appears to trade-off against natal cooperation. Our findings thus highlight that the evolution of sex differences in cooperation could be widely attributable to trade-offs between cooperation and dispersal; a potentially general explanation that does not demand that cooperation yields direct fitness benefits.

evolutionary biology↗

bioRxiv2023

Fusogenic Structural Changes in Arenavirus Glycoproteins are Associated with Viroporin Activity

Many enveloped viruses enter host cells by fusing with acidic endosomes. The fusion activity of multiple viral envelope glycoproteins does not generally affect viral membrane permeability. However, fusion induced by the Lassa virus (LASV) glycoprotein complex (GPc) is always preceded by an increase in viral membrane permeability and the ensuing acidification of the virion interior. Here, systematic investigation of "leaky" LASV fusion using single pseudoparticle tracking in live cells reveals that the change in membrane barrier function is associated with the fusogenic conformational reorganization of GPc. We show that a small- molecule fusion inhibitor or mutations that impair viral fusion by interfering with GPc refolding into the post-fusion structure prevent the increase in membrane permeability. We find that the increase in virion membrane permeability occurs early during endosomal maturation and is facilitated by virus-cell contact. This increase is observed using diverse arenavirus glycoproteins, whether presented on lentivirus-based pseudoviruses or arenavirus-like particles, and in multiple different cell types. Collectively, these results suggest that conformational changes in GPc triggered by low pH and cell factor binding are responsible for virion membrane permeabilization and acidification of the virion core prior to fusion. We propose that this viroporin-like activity may augment viral fusion and/or post-fusion steps of infection, including ribonucleoprotein release into the cytoplasm. Authors summaryFusion of enveloped virus with host cell membranes is mediated by extensive conformational changes in viral glycoproteins, triggered by binding to cognate receptors and/or by exposure to acidic pH in the maturing endosome. We have previously reported that, unlike many other viral glycoproteins, pH-triggered endosomal fusion by the Lassa virus viral glycoprotein complex (GPc) is preceded by a mild permeabilization of the viral membrane. Here, we provide evidence that this activity is associated with early fusogenic changes in the GPc and is markedly enhanced by virus-cell contact. Permeabilization is induced by the glycoproteins of diverse arenaviruses and occurs in multiple target cell types. Based on these observations, we propose that, by analogy to the influenza virus M2 channel, membrane permeabilization and the resultant acidification of the arenavirus interior facilitate viral fusion and/or post-fusion steps of infection.

microbiology↗

bioRxiv2022

Signaling modality within gp130 receptor enhances tissue regeneration

Adult mammals are incapable of multi-tissue regeneration and augmentation of this potential may drastically shift current therapeutic paradigms. Here, we found that a common co-receptor of IL-6 cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) exhibit regenerative, not reparative, responses after wounding in skin and anti-degenerative responses in the synovial joint. In addition, pharmacological inhibition of gp130 Y814 results in regeneration of multiple tissues in several species as well as disease modification in animal models of osteoarthritis. Our study characterizes a novel molecular mechanism that, if selectively manipulated, enhances the intrinsic regenerative capacity while preventing pathological outcomes in injury and disease. SummaryGp130 Y814 signaling module serves as a cellular stress sensor responsible for hindering tissue regeneration while triggering pathological outcomes after injury.

molecular biology↗