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Science (New York, N.Y.) Sep 2023CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies...
CDC45-MCM2-7-GINS (CMG) helicase assembly is the central event in eukaryotic replication initiation. In yeast, a multi-subunit "pre-loading complex" (pre-LC) accompanies GINS to chromatin-bound MCM2-7, leading to CMG formation. Here, we report that DONSON, a metazoan protein mutated in microcephalic primordial dwarfism, is required for CMG assembly in vertebrates. Using AlphaFold to screen for protein-protein interactions followed by experimental validation, we show that DONSON scaffolds a vertebrate pre-LC containing GINS, TOPBP1, and DNA pol ε. Our evidence suggests that DONSON docks the pre-LC onto MCM2-7, delivering GINS to its binding site in CMG. A patient-derived DONSON mutation compromises CMG assembly and recapitulates microcephalic dwarfism in mice. These results unify our understanding of eukaryotic replication initiation, implicate defective CMG assembly in microcephalic dwarfism, and illustrate how in silico protein-protein interaction screening accelerates mechanistic discovery.
Topics: Animals; Humans; Mice; Cell Cycle Proteins; DNA Replication; DNA-Binding Proteins; Minichromosome Maintenance Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Protein Interaction Mapping; Computer Simulation; Nuclear Proteins; Dwarfism; Microcephaly; Xenopus laevis
PubMed: 37590370
DOI: 10.1126/science.adi3448 -
Philosophical Transactions of the Royal... Jul 2023Animal defences against infection involve two distinct but complementary mechanisms: tolerance and resistance. Tolerance measures the animal's ability to limit... (Review)
Review
Animal defences against infection involve two distinct but complementary mechanisms: tolerance and resistance. Tolerance measures the animal's ability to limit detrimental effects from a given infection, whereas resistance is the ability to limit the intensity of that infection. Tolerance is a valuable defence for highly prevalent, persistent or endemic infections where mitigation strategies based on traditional resistance mechanisms are less effective or evolutionarily stable. Selective breeding of amphibians for enhanced tolerance to spp has been suggested as a strategy for mitigating the impacts of the fungal disease, chytridiomycosis. Here, we define infection tolerance and resistance in the context of chytridiomycosis, present evidence for variation in tolerance to chytridiomycosis, and explore epidemiological, ecological and evolutionary implications of tolerance to chytridiomycosis. We found that exposure risk and environmental moderation of infection burdens are major confounders of resistance and tolerance, chytridiomycosis is primarily characterized by variation in constitutive rather than adaptive resistance, tolerance is epidemiologically important in driving pathogen spread and maintenance, heterogeneity of tolerance leads to ecological trade-offs, and natural selection for resistance and tolerance is likely to be dilute. Improving our understanding of infection tolerance broadens our capacity for mitigating the ongoing impacts of emerging infectious diseases such as chytridiomycosis. This article is part of the theme issue 'Amphibian immunity: stress, disease and ecoimmunology'.
Topics: Animals; Mycoses; Amphibians; Biological Evolution; Communicable Diseases, Emerging; Immune Tolerance
PubMed: 37305912
DOI: 10.1098/rstb.2022.0133 -
Cell Feb 2024Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which...
Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains, and greater morphological diversity. Here, we report that RNA-level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination. We show that RNLTR12-int-encoded RNA binds to the transcription factor SOX10 to regulate transcription of myelin basic protein (Mbp, the major constituent of myelin) in rodents. RNLTR12-int-like sequences (which we name RetroMyelin) are found in all jawed vertebrates, and we further demonstrate their function in regulating myelination in two different vertebrate classes (zebrafish and frogs). Our study therefore suggests that retroviral endogenization played a prominent role in the emergence of vertebrate myelin.
Topics: Animals; Gene Expression; Myelin Sheath; Oligodendroglia; Retroelements; RNA; Zebrafish; Anura
PubMed: 38364788
DOI: 10.1016/j.cell.2024.01.011 -
BioRxiv : the Preprint Server For... Apr 2024Cancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species...
Cancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight (contrary to Petos Paradox) and somatic mutation rate, but decreases with gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.
PubMed: 36824942
DOI: 10.1101/2023.02.15.527881 -
Seminars in Nuclear Medicine Sep 2023The bulk of biomedical positron emission tomography (PET)-scanning experiments are performed on mammals (ie, rodents, pigs, and dogs), and the technique is only... (Review)
Review
The bulk of biomedical positron emission tomography (PET)-scanning experiments are performed on mammals (ie, rodents, pigs, and dogs), and the technique is only infrequently applied to answer research questions in ectothermic vertebrates such as fish, amphibians, and reptiles. Nevertheless, many unique and interesting physiological characteristics in these ectothermic vertebrates could be addressed in detail through PET. The low metabolic rate of ectothermic animals, however, may compromise the validity of physiological and biochemical parameters derived from the images created by PET and other scanning modalities. Here, we review some of the considerations that should be taken into account when PET scanning fish, amphibians, and reptiles. We present specific results from our own experiments, many of which remain previously unpublished, and we draw on examples from the literature. We conclude that knowledge on the natural history and physiology of the species studied and an understanding of the limitations of the PET scanning techniques are necessary to avoid the design of faulty experiments and erroneous conclusions.
Topics: Animals; Swine; Dogs; Vertebrates; Reptiles; Amphibians; Fishes; Positron-Emission Tomography; Mammals
PubMed: 37438172
DOI: 10.1053/j.semnuclmed.2023.06.006 -
PeerJ 2023Wildlife farming can be an important but complex tool for conservation. To achieve conservation benefits, wildlife farming should meet a variety of criteria, including... (Review)
Review
BACKGROUND
Wildlife farming can be an important but complex tool for conservation. To achieve conservation benefits, wildlife farming should meet a variety of criteria, including traceability conditions to identify the animals' origin. The traditional techniques for discriminating between wild and captive animals may be insufficient to prevent doubts or misdeclaration, especially when labels are not expected or mandatory. There is a pressing need to develop more accurate techniques to discriminate between wild and captive animals and their products. Stable isotope analysis has been used to identify animal provenance, and some studies have successfully demonstrated its potential to differentiate wild from captive animals. In this literature review, we examined an extensive collection of publications to develop an overall picture of the application of stable isotopes to distinguish between wild and captive animals focusing on evaluating the patterns and potential of this tool.
SURVEY METHODOLOGY
We searched peer-reviewed publications in the Web of Science database and the references list from the main studies on the subject. We selected and analyzed 47 studies that used C, N, H, O, and S in tissues from fish, amphibians, reptiles, birds, and mammals. We built a database from the isotope ratios and metadata extracted from the publications.
RESULTS
Studies have been using stable isotopes in wild and captive animals worldwide, with a particular concentration in Europe, covering all main vertebrate groups. A total of 80.8% of the studies combined stable isotopes of carbon and nitrogen, and 88.2% used at least one of those elements. Fish is the most studied group, while amphibians are the least. Muscle and inert organic structures were the most analyzed tissues (46.81% and 42.55%). C and N standard deviation and range were significantly higher in the wild than in captive animals, suggesting a more variable diet in the first group. C tended to be higher in wild fishes and in captive mammals, birds, reptiles, and amphibians. N was higher in the wild terrestrial animals when controlling for diet. Only 5.7% of the studies failed to differentiate wild and captive animals using stable isotopes.
CONCLUSIONS
This review reveals that SIA can help distinguish between wild and captive in different vertebrate groups, rearing conditions, and methodological designs. Some aspects should be carefully considered to use the methodology properly, such as the wild and captivity conditions, the tissue analyzed, and how homogeneous the samples are. Despite the increased use of SIA to distinguish wild from captive animals, some gaps remain since some taxonomic groups (., amphibians), countries (., Africa), and isotopes (., H, O, and S) have been little studied.
Topics: Animals; Carbon Isotopes; Nitrogen Isotopes; Animals, Wild; Carbon; Fishes; Mammals
PubMed: 38025752
DOI: 10.7717/peerj.16460 -
Current Opinion in Neurobiology Oct 2023The transition from larval to adult locomotion in the anuran, Xenopus laevis, involves a dramatic switch from axial to appendicular swimming including intermediate... (Review)
Review
The transition from larval to adult locomotion in the anuran, Xenopus laevis, involves a dramatic switch from axial to appendicular swimming including intermediate stages when the tail and hindlimbs co-exist and contribute to propulsion. Hatchling tadpole swimming is generated by an axial central pattern generator (CPG) which matures rapidly during early larval life. During metamorphosis, the developing limbs are controlled by a de novo appendicular CPG driven initially by the axial system before segregating to allow both systems to operate together or independently. Neuromodulation plays important roles throughout, but key modulators switch their effects from early inhibitory influences to facilitating locomotion. Temperature affects the construction and operation of locomotor networks and global changes in environmental temperature place aquatic poikilotherms, like amphibians, at risk. The locomotor control strategy of anurans differs from other amphibian groups such as salamanders, where evolution has acted upon the thyroid hormone pathway to sculpt different developmental outcomes.
Topics: Animals; Spinal Cord; Larva; Locomotion; Swimming; Anura; Metamorphosis, Biological
PubMed: 37549591
DOI: 10.1016/j.conb.2023.102753 -
Developmental Cell Nov 2023Axolotl limb regeneration is accompanied by the transient induction of cellular senescence within the blastema, the structure that nucleates regeneration. The precise...
Axolotl limb regeneration is accompanied by the transient induction of cellular senescence within the blastema, the structure that nucleates regeneration. The precise role of this blastemal senescent cell (bSC) population, however, remains unknown. Here, through a combination of gain- and loss-of-function assays, we elucidate the functions and molecular features of cellular senescence in vivo. We demonstrate that cellular senescence plays a positive role during axolotl regeneration by creating a pro-proliferative niche that supports progenitor cell expansion and blastema outgrowth. Senescent cells impact their microenvironment via Wnt pathway modulation. Further, we identify a link between Wnt signaling and senescence induction and propose that bSC-derived Wnt signals facilitate the proliferation of neighboring cells in part by preventing their induction into senescence. This work defines the roles of cellular senescence in the regeneration of complex structures.
Topics: Animals; Ambystoma mexicanum; Cellular Senescence; Wnt Signaling Pathway; Stem Cells; Cell Proliferation; Extremities
PubMed: 37879337
DOI: 10.1016/j.devcel.2023.09.009