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PubMed2026

A Young ahsg/fetuin-a Inactive Retrocopy Reflects Recent Retrotransposon Activity in the Xenopus laevis Lineage.

The vertebrate ahsg (alpha 2-HS glycoprotein, also coined fetuin-a) homologs are highly expressed in the liver, and their secreted protein products exert complex systemic effects, including the regulation of biomineralization of soft and skeletal tissues. Here, we report a previously uncharacterized ahsg retrocopy in the allotetraploid frog species Xenopus laevis. We show that this young retrocopy was born from the ahsg.L homeologue less than 10 Mya, and landed in the S subgenome in a locus located between asic2.S and smarcd2.S. The ahsg.L-retrocopy ends with a poly(A) tail, is intronless, and is flanked by target site duplications. While the ahsg.L-retrocopy's ORF is devoid of frameshifts and nonsense mutations, it suffers from a short 5' deletion, eliminating the original start codon and the signal peptide. Remarkably, this truncated ORF lies in frame with an ATG codon contributed by the neighboring genomic sequence, suggesting that the ahsg.L-retrocopy might potentially be expressed and translated into a protein product. Nevertheless, examination of RNA-Seq and proteomic experiments respectively performed on liver and bone tissues did not provide expression evidence for the ahsg.L-retrocopy. We propose that, in spite of its rescued ORF, the ahsg.L-retrocopy is non-functional and can be considered a young pseudogene born from recent retrotransposon activity in the Xenopus laevis lineage.

Animals↗
PubMed2025

Clinical and electrophysiological characterization of a SCN5A gain-of-function mutation associated with CPVT-like arrhythmia.

The present study aimed to characterize the SCN5A variant I1333V, found in five families with a history of suspected catecholaminergic polymorphic ventricular tachycardia (CPVT). SCN5A encodes the pore-forming subunit of the cardiac voltage-gated sodium channel NaV1.5. Gain of SCN5A function causes long QT syndrome type 3 (LQT3), but its involvement in CPVT is disputed. Nineteen patients harboring the I1333V variant were identified across five families, commonly presenting with exercise-induced arrhythmia, including polymorphic premature ventricular contractions, ventricular bigeminy, couplets, and ventricular tachycardias. Prolonged QT interval was a less consistent finding, and structural myocardial changes were absent. Human NaV1.5/β1 complexes were expressed in Xenopus laevis oocytes, using RNA combinations to emulate homozygous wild-type, heterozygous and homozygous I1333V-mutant conditions. Cells were studied using the cut-open oocyte Vaseline gap voltage-clamp to evaluate effects of I1333V on NaV1.5 function. NaV1.5(I1333V) channels required less depolarization to activate, classifying this variant as gain-of-function. Fast inactivation was unaffected, and action-potential (AP) clamp showed no significant differences in late Na+ current. A computational model of human ventricular myocyte excitability predicted no effect of I1333V on AP duration; instead, it showed stronger Na+ influx during the AP upstroke, concurrent with elevated Ca2+ import via the sodium‑calcium exchanger. Finally, NaV1.5(I1333V) channels exhibited a diminished response to cAMP (emulating adrenergic stimulation), which also likely contributes to arrhythmogenesis. In conclusion, I1333V is a gain-of-function variant of SCN5A with a unique set of functional consequences. It is associated with cardiac arrhythmia disease characterized by overlapping CPVT-like and LQT3 features. Our findings support that SCN5A should be considered in genetic screening of suspected CPVT.

NAV1.5 Voltage-Gated Sodium Channel↗
PubMed2024

Specificity profiling of deubiquitylases against endogenously generated ubiquitin-protein conjugates.

Deubiquitylating enzymes (DUBs) remove ubiquitin from proteins thereby regulating their stability or activity. Our understanding of DUB-substrate specificity is limited because DUBs are typically not compared to each other against many physiological substrates. By broadly inhibiting DUBs in Xenopus egg extract, we generated hundreds of ubiquitylated proteins and compared the ability of 30 DUBs to deubiquitylate them using quantitative proteomics. We identified five high-impact DUBs (USP7, USP9X, USP36, USP15, and USP24) that each reduced ubiquitylation of over 10% of the isolated proteins. Candidate substrates of high-impact DUBs showed substantial overlap and were enriched for disordered regions, suggesting this feature may promote substrate recognition. Other DUBs showed lower impact and non-overlapping specificity, targeting distinct non-disordered proteins including complexes such as the ribosome or the proteasome. Altogether our study identifies candidate DUB substrates and defines patterns of functional redundancy and specificity, revealing substrate characteristics that may influence DUB-substrate recognition.

Substrate Specificity↗
PubMed2024

A time-resolved single-cell roadmap of the logic driving anterior neural crest diversification from neural border to migration stages.

Neural crest cells exemplify cellular diversification from a multipotent progenitor population. However, the full sequence of early molecular choices orchestrating the emergence of neural crest heterogeneity from the embryonic ectoderm remains elusive. Gene-regulatory-networks (GRN) govern early development and cell specification toward definitive neural crest. Here, we combine ultradense single-cell transcriptomes with machine-learning and large-scale transcriptomic and epigenomic experimental validation of selected trajectories, to provide the general principles and highlight specific features of the GRN underlying neural crest fate diversification from induction to early migration stages using Xenopus frog embryos as a model. During gastrulation, a transient neural border zone state precedes the choice between neural crest and placodes which includes multiple converging gene programs. During neurulation, transcription factor connectome, and bifurcation analyses demonstrate the early emergence of neural crest fates at the neural plate stage, alongside an unbiased multipotent-like lineage persisting until epithelial-mesenchymal transition stage. We also decipher circuits driving cranial and vagal neural crest formation and provide a broadly applicable high-throughput validation strategy for investigating single-cell transcriptomes in vertebrate GRNs in development, evolution, and disease.

Animals↗
PubMed2026

Glycogen-dependent demixing of frog egg cytoplasm at increased crowding.

Crowding increases the tendency of macromolecules to aggregate and phase separate, and regulated crowding contributes to subcellular organization and stress response. To explore the effect of crowding in a well-characterized model cytoplasm, we developed methods to concentrate the macromolecule components of Xenopus egg extracts without changing small molecules. Egg cytoplasm contains a high concentration of glycogen that serves as an energy store for early development. When crowding was increased 1.4×, the egg cytoplasm demixed into two liquid phases of approximately equal volume, one of which was highly enriched in glycogen. Glycogen hydrolysis prevented and reversed demixing. Quantitative proteomics showed that the glycogen-rich phase was enriched in proteins that bind glycogen, participate in carbohydrate metabolism, or are part of very high-molecular-weight complexes. The glycogen-depleted phase was enriched in ribosomes, endoplasmic reticulum (ER), and mitochondria. Smaller soluble proteins were approximately equipartitioned. Glycogen is usually observed in aggregates in intact cells, and recent work suggested a role for phase separation in its localization. Our results show that glycogen particles can spontaneously demix and suggest that demixing may be regulated by crowding.

Animals↗
PubMed2026

Spatially ordered zygotic genome activation fulfills embryo quality control.

Early embryo development features autonomous, maternally driven cell divisions that self-organize the multicellular blastula or blastocyst tissue. Maternal control cedes to the zygote starting with the onset of widespread zygotic genome activation (ZGA), which is essential for subsequent cell fate determination and morphogenesis. Intriguingly, although ZGA onset is highly regulated at the level of the whole embryo, it can be non-homogenous and precisely patterned at the single-cell level. We previously demonstrated a stereotyped spatial and temporal ordering of ZGA in a model vertebrate embryo. Unknown, however, was whether this precise ZGA patterning was required for development. To address this fundamental question, we devised a strategy to spatially control cell divisions that perturb blastula embryo organization. We demonstrate the feasibility of spatially inverting the cell size pattern of embryos and find that these inverted embryos exhibit a flipped pattern of ZGA. Mispatterned ZGA along the animal-vegetal axis triggers embryo apoptosis, revealing that gastrula embryos have a built-in quality control system to sense inappropriate ZGA patterning, including regionalized defects in transcriptional onset. The quality control response is nonautonomous, dependent on an anti-apoptotic signal that suppresses cell death outside the animal hemisphere. These results reveal the requirement of properly patterned ZGA for normal development and the existence of a surveillance system of embryo quality control exquisitely tuned to the spatial and temporal ordering of genome activation and zygotic gene expression.

Animals↗
PubMed2025

Foxi2 and Sox3 are master transcription regulators that control ectoderm germ layer specification in Xenopus.

Germ layer specification represents a critical transition where pluripotent cells acquire lineage-specific identities. We identify the maternal transcription factors Foxi2 and Sox3 to be pivotal master regulators of ectodermal germ layer specification in Xenopus. Ectopic co-expression of Foxi2 and Sox3 in prospective endodermal tissue induces the expression of ectodermal markers while suppressing mesendodermal markers. Transcriptomic analyses reveal that Foxi2 and Sox3 jointly and independently regulate hundreds of ectodermal target genes. During early cleavage stages, Foxi2 and Sox3 pre-bind to key cis-regulatory modules (CRMs), marking sites that later recruit Ep300 and facilitate H3K27ac deposition, thereby shaping the epigenetic landscape of the ectodermal genome. These CRMs are highly enriched within ectoderm-specific super-enhancers (SEs). Our findings highlight the pivotal role of ectodermal SE-associated CRMs in precise and robust ectodermal gene activation, establishing Foxi2 and Sox3 as central architects of ectodermal lineage specification.

Animals↗