The autopod, the distal region of tetrapod limbs, represents a key evolutionary innovation requiring coordinated patterning, proliferation, and morphogenetic processes. While avian digit individualization has classically been described as driven almost exclusively by Programmed Cell Death (PCD) in the interdigital zone (IDZ), evidence from basal tetrapods indicates that differential growth between the digital zone (DZ) and IDZ originally mediated digit separation without apoptotic involvement. It remains unclear if this ancestral mechanism persists in amniotes or has been evolutionarily replaced by apoptosis. Here, we investigated growth dynamics in chicken (Gallus gallus) embryos by combining quantitative extension analyses, fluorescent DiI lineage tracing, and PH3-based proliferation assays. We demonstrate that differential growth is conserved in amniotes and arises through dynamic divergence in DZ and IDZ behaviour in chicken embryos. In chicken, although both regions expand comparably until HH32, IDZ extension declines markedly thereafter, while DZ outgrowth continues uninterrupted. DiI lineage tracing shows that the medial and proximal IDZ regions exhibit significantly greater extension at HH32 than at HH34, indicating a developmental decrease in growth that does not occur in the DZ, which maintains higher, stable extension rates across stages. Proliferation analyses align with these morphometric findings: the IDZ shows a sharp reduction in PH3-positive cells post-HH32, establishing a proliferative deficit relative to the DZ. Examination along the proximodistal axis revealed that the distal IDZ, influenced by the AER, shows the greatest proliferative activity, whereas medial and proximal regions contain fewer proliferative cells; this gradient is absent in the DZ, which displays relatively uniform proliferation. Together, these results indicate that avian digit separation is not governed solely by apoptosis but is initiated by an intrinsic decline in IDZ extension and cell-cycle activity. We propose that birds retain the ancestral differential growth mechanism, which works in concert with apoptosis to refine digit boundaries, bridging the evolutionary bridge between amphibian-like growth-driven individualization and amniote apoptotic refinement.
BACKGROUND:Although many genes have been implicated in spermatogenesis, their precise relationships to male fertility remain unclear. Here, we investigated the in vivo importance of the highly conserved, testis-enriched gene Samd7 as a potential regulator of murine spermatogenesis and fertility. METHODS:Samd7-/- mice were generated using CRISPR/Cas9. qPCR was used to assess Samd7 mRNA expression across mouse tissues. SAMD7 protein levels in testis were examined by Western blotting. Hematoxylin and eosin (H&E) staining of testis and epididymis was performed to evaluate spermatogenesis and sperm maturation. Immunofluorescence was used to characterize developmental stages of germ cells in the testis. Computer-assisted sperm analysis (CASA) was employed to measure sperm motility and related parameters. RESULTS:Samd7 expression was enriched in testis beginning at postnatal week 3. Compared with wild-type (Samd7+/+) littermates, Samd7-/- males showed no abnormalities in sperm content, testicular morphology, or fertility. Histology confirmed intact seminiferous tubules and normal testicular architecture in both Samd7+/+ and Samd7-/- mice. No differences were detected in sperm morphology or motility, including swimming velocity, in Samd7-/- mice. Testes and epididymides from Samd7-/- animals contained the expected spectrum of germ cells-from spermatogonia to mature spermatozoa-consistent with unimpaired spermatogenesis. CONCLUSIONS:These findings indicate that Samd7 is dispensable for murine spermatogenesis and male fertility under standard laboratory conditions.
The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.
BACKGROUND:Endometriosis is sustained by ectopic endometrial implants that remain proliferative and vascularized, making endocrine modulation a cornerstone of therapy. Estetrol (E4) an endogenous estrogen produced during pregnancy, with selective tissue activity, may modulate progesterone (P4) outputs in ectopic tissue and potentially shift lesion biology toward growth restraint without reinforcing vascular support. OBJECTIVE:To test whether E4 modifies P4 effects on lesion proliferation, apoptosis-related signaling, and angiogenic/endothelial activation in vivo. METHODS:Hormonally intact female mice bearing allografted endometriotic lesions received vehicle, E4 (3 mg/day), P4 (4.25 mg/day), or E4 + P4 once daily for 14 days. Lesions and eutopic endometrium were assessed by immunohistochemistry (Ki-67, cleaved caspase-3, BAX, VEGF, PECAM-1/CD31, Cyclin D1) with epithelial/stromal quantification, and endothelial angiogenic behavior was evaluated using a tube-formation assay. RESULTS:Lesions exhibited higher proliferative activity than eutopic endometrium. P4 reduced lesion proliferation, and the E4 + P4 combination produced the strongest growth restraint. Apoptosis-related markers increased under endocrine treatments, with the combined regimen showing robust activation. Notably, P4 enhanced angiogenesis-related readouts (VEGF and PECAM/CD31), whereas E4 + P4 prevented these increases and reduced endothelial tube formation, consistent with attenuated endothelial activation under the combined regimen. CONCLUSIONS:The E4-P4 combination supports a "balanced" endocrine profile-robust growth restraint without concurrent endothelial activation-thereby decoupling proliferation restraint from angiogenic activation.
Schizophrenia is a neurodevelopmental disorder associated with alterations in neuronal function and connectivity. It has been extensively modeled using neurons derived from induced pluripotent stem cells (iPSC), where significant differences between patients and healthy controls have been reported. Notably, spontaneous generation of astrocytes in these cultures can influence functional and molecular analyses. This study assesses whether schizophrenia (SZ) and healthy control (HC) iPSC-derived neuronal cultures significantly differ in their cellular composition and determines how these variations impact transcriptomic interpretations. iPSC from three HC and four SZ were differentiated into neuronal cultures and then characterized using immunostaining, RNA sequencing, transcriptomic deconvolution, and flow cytometry. Transcriptomic analysis identified differential gene expression in SZ cultures, enriched gene ontology (GO) pathways related to neurodevelopment and synaptic function. Additionally, SynGO analysis revealed altered expression of genes associated with pre- and postsynaptic compartments. Cell-type deconvolution showed enrichment of immature and postmitotic neuronal populations in SZ cultures, whereas HC cultures displayed higher astrocyte enrichment. The neuronal enrichment was further supported by flow cytometry, which indicated an increased proportion of NeuN-positive nuclei in SZ-derived cultures. Together, our results support a model where a shift in the neuronal-glial balance in schizophrenia neural cell populations may contribute to the disease-associated phenotypes.
Toll-like receptors (TLRs) were first identified as developmental cues that establish the dorsal-ventral axis in Drosophila. This discovery was followed by the recognition of their central role in invertebrate and vertebrate innate immunity. Here we review an additional set of discoveries that establishes the role of TLRs in epithelial tissue dynamics and surveillance in Drosophila. A growing body of work reveals that, largely independent of their canonical signalling, TLRs guide tissue mechanics. Spatial patterns of TLR localisation control collective cell movements and large-scale morphogenesis by modulating cell contractility. Intriguingly, the same TLRs also enable tissues to recognise and remove unfit or misplaced cells, revealing their essential function in tissue surveillance during development. Across these contexts, TLRs act as sensors that integrate positional information, mechanical forces, and cell identity. By tracing the path from early embryonic patterning to immunity, mechanics and finally tissue surveillance, this review highlights how the evolutionarily conserved TLR family continues to refine our understanding of how tissues shape, maintain, and protect themselves.
INTRODUCTION:Adenylyl cyclase (AC) is an important enzyme that mediates stem cells' response to hormonal stimuli. Despite the fact that currently there are ten described isoforms of AC little is known about their individual significance in different aspects of stem cell functions control. This study focuses on elucidating the significance of AC isoforms in the control of multipotent mesenchymal stromal cells (MSCs) differentiation. We investigated changes in adenylyl cyclase expression (ADCY) during adipogenic and osteogenic differentiation of MSCs. Our results suggest that the expression only of ADCY1 elevates during MSCs' both osteogenic and adipogenic differentiations. RESULTS:We used the CRISPR/Cas9 D10A system to knock out the ADCY1 gene in MSCs. The ADCY1 knockout MSC cell line demonstrated reduced ADCY1 expression in the undifferentiated state compared to control cells. Moreover, ADCY1 expression in the ADCY1-KO cell line didn't increase during the differentiation process, which confirms the successful knockout. The ADCY1-KO cell line demonstrated an impaired differentiation potential in both adipogenic and osteogenic directions. However, the ability for adipogenic differentiation was restored by a direct PPARγ agonist addition. CONCLUSIONS:Our findings indicate that ADCY1 expression upregulation is critical for MSC differentiation into osteogenic and adipogenic lineages.
Breast Cancer Gene 1 (BRCA1) is a critical regulator of genome integrity whose dysfunction greatly increases lifetime risk of breast and ovarian cancers. While BRCA1 has been extensively studied in the contexts of adult biology and cancer, its diverse functions, including homologous recombination-mediated DNA repair, cell cycle checkpoint activation, protein ubiquitination, and transcriptional regulation, have many underexplored implications. In early embryonic development, the maternal-to-zygotic transition (MZT) and subsequent developmental processes place extraordinary demands on DNA replication fidelity, cell cycle regulation, transcriptional activation, and chromatin remodeling. These critical processes overlap strikingly with canonical functions of BRCA1, yet its function in early development is poorly characterized. In this review, we investigate BRCA1 conservation across species and connect its well-established functions to findings from developmental studies to assess its role in development. We highlight evidence of BRCA1 mitigating genome integrity loss from diverse sources, maintaining the proliferative activity needed for successful germ layer formation and early tissue morphogenesis, and regulating transcription and epigenetic modifications. Together, this synthesis supports a model where BRCA1 acts as a multi-functional and dynamic regulator of early embryogenesis. Building on this, we propose outstanding questions that could further illuminate these developmental roles. Characterization of BRCA1 in early development may not only provide important insight into the origin and progression of cancer susceptibility but may also elucidate fundamental mechanisms shaping early development.
Facial ageing manifests in highly consistent, topologically predictable patterns, including nasolabial folds and tear troughs, despite wide inter-individual variation in anatomy and soft-tissue volume loss. Current clinical models emphasise adult structural changes but do not explain why age-related features localise to invariant facial interfaces or why corrective interventions often plateau. We hypothesised that lifelong facial mechanics are constrained by boundary domains established during embryonic morphogenesis and preserved throughout life. To investigate this, we developed a data-constrained 4D mechanochemical growth model of human facial development, anchored to three-dimensional Carnegie stage atlases (CS7-CS23) and whole-embryo imaging datasets. A virtual cohort of 5000 individuals was generated using statistical shape dynamics and diffeomorphic registration. The model simulated neural crest-driven patterning, extracellular matrix maturation, branchiomeric myogenesis, and neurovascular routing. An adherence-domain score, integrating stiffness, shear resistance, and temporal persistence, was used to identify emergent embryonic boundary precursors. Stabilised boundary domains emerged by Carnegie stage 16 in 87.4% of simulations and remained positionally invariant thereafter (mean centroid drift <1 mm). These domains predicted known adult retaining ligament locations and showed 91.6% spatial overlap with simulated neurovascular trajectories. Perioral and periorbital regions exhibited two- to threefold higher stiffness anisotropy than malar and frontal regions. Muscle fibres aligned preferentially with pre-patterned connective corridors, and simulated surface-level interventions reduced peak strain without displacing boundary position in 98.7% of cases. These findings indicate that facial ageing reflects the amplification of embryonically encoded mechanical boundaries rather than the de novo formation of folds. This developmental-mechanistic framework explains invariant ageing patterns and clarifies the limitations of volume-centric aesthetic strategies.
Gestational diabetes mellitus (GDM) is characterized by insulin resistance (IR) and impaired glucose tolerance during pregnancy, yet the upstream regulatory mechanisms controlling insulin signaling remain unclear. The circular RNA hsa_circ_0039480 (circNUP93) has been proposed as a potential biomarker for GDM, but its functional role in disease progression is poorly understood. A high-fat diet-induced GDM mouse model and insulin-resistant HTR-8/SVneo trophoblast cell model were used to investigate the role of circNUP93. Knockdown experiments were performed to assess effects on glucose metabolism and insulin signaling. miR-767-3p was identified as a downstream target of circNUP93 through bioinformatic prediction and validated via RNA pulldown, FISH, and dual-luciferase reporter assays. HIF1A was confirmed as a miR-767-3p target using TargetScan and functional assays. Rescue experiments were used to validate the circNUP93/miR-767-3p/HIF1A axis in trophoblast cells. circNUP93 was significantly upregulated in the serum and placentas of GDM mice. The knockdown of circNUP93 improved glucose metabolism, reduced lipid abnormalities, and alleviated IR. Mechanistically, circNUP93 functioned as a molecular sponge for miR-767-3p, which directly targeted HIF1A. Silencing circNUP93 upregulated miR-767-3p, suppressed HIF1A expression, and restored the insulin signaling. In vitro, circNUP93 knockdown promoted glucose uptake and improved cell viability, migration, and invasion under insulin-resistant conditions. Overall, this study identified the circNUP93/miR-767-3p/HIF1A axis as a novel regulatory mechanism contributing to IR and trophoblast dysfunction in GDM.
This study systematically evaluates several deep learning-based segmentation networks for zebrafish image analysis. With the same dataset and preprocessing procedures, we selected eleven representative segmentation models, including U-Net, SegNet, PSPNet, DeepLabv3+, Attention U-Net, HRNet, SegFormer, MASNet, the Segment Anything Model (SAM), PVT-EMCAD, and RWKV-UNet. We comprehensively compared their performance via various evaluation metrics, such as Dice coefficient, intersection-over-union, and mean pixel accuracy. Qualitative evaluations are combined with quantitative ones to compare and analyze the models’ effectiveness in detecting intricate organ structures and phenotypic anomalies among zebrafish. The experimental results show that high-resolution maintenance, context-aggregation mechanisms, and attention mechanisms are the keys to improving the accuracy of small structure detection and boundary delineation, and the Transformer architecture also shows significant advantages in global dependency modeling. This study provides a general technique and theoretical support for high-throughput toxicological screening and morphological quantification of zebrafish images.
In contrast to humans, zebrafish have an outstanding ability to regenerate injured heart through a highly orchestrated process involving all cardiac structures. To replace the lost myocardium, resident cardiomyocytes (CMs) dedifferentiate and proliferate, invading the injured area. The response of the myocardium is preceded by the activation of the epicardium and endocardium, which form active scaffolds to provide mechanical and paracrine support to guide regeneration. New CMs use protrusions to migrate and invade fibrotic injured tissue, replacing it with functional myocardium. Here, we investigated the expression profile of the stress-responsive ankrd1a gene in different cardiac structures, at key time points during regeneration, aiming to gain insight into its precise roles during zebrafish heart regeneration. In the TgBAC(ankrd1a:EGFP) reporter line, transgene upregulation was restricted to the myocardium, initiated as early as 15 h post-cryoinjury, and consistently marked CMs bordering the injury or scar area during regeneration. Transcriptome profiling and immunostaining revealed a potential role of ankrd1a in regulating CMs' dedifferentiation, as well as changes in the expression of genes associated with antigen presentation and extracellular matrix composition in the ankrd1a mutant. Our results indicate that ankrd1a is dispensable for ventricular regeneration after cryoinjury, while it may serve as a marker and fine-tuner in the healing process of injured cardiac muscle.
The zebrafish (Danio rerio) has become a popular model organism in developmental biology, but the high costs of commercial housing systems often limit accessibility for resource-constrained research and educational purposes. Here, we introduce ZebRack, an open-source, budget-friendly mobile zebrafish housing system designed to support autonomous maintenance and breeding during short term periods. Built for under US$900, this modular 15-tank setup features 2.8 L tanks integrated into a compact, mobile framework with recirculating water filtration and adjustable flow rates. The system prioritizes cost-efficiency through off-the-shelf hardware and components while ensuring water quality via a three-stage filtration process (mechanical, biological, and chemical). Temperature is precisely controlled using a submersible water heater and can be complemented with a portable air conditioning unit to maintain optimal conditions. ZebRack demonstrated robust performance in a proof-of-principle trial during the 2025 International Developmental Biology Course in Quintay, Chile. Operated within an indoor culture tent, the system enabled daily embryo production via an integrated electric photoperiod system to synchronize breeding cycles. The modular design of ZebRack allows for quick setup and configuration, accommodating diverse experimental or teaching needs, while its portability and small footprint make it ideal for laboratories with limited space or temporary setups. By combining affordability with open-access design specifications, validated thermal stability, and field-tested breeding efficiency, this system adds flexibility to current zebrafish husbandry infrastructure. Detailed assembly guides and part lists are freely available to promote global adoption, fostering equitable access to zebrafish-based research and education.
The inability of damaged neurons to regenerate poses a significant challenge in the repair of peripheral nerve injuries. Exogenous cell therapies, such as those involving neural stem cells or induced pluripotent stem cells, are limited by immune rejection and ethical concerns. Somatic cells offer a promising alternative, as they can be reprogrammed and differentiated into neuron-like cells, thereby promoting nerve repair. Satellite glial cells (SGCs) within the dorsal root ganglion (DRG) have the capacity to differentiate into multiple cell types. In this study, chemical small molecules were used to replace transcription factors and induce DRG-derived SGCs to differentiate into sensory neuron-like cells. Subsequently, cell viability, morphology, and functionality were evaluated using CCK-8 assays, immunocytochemistry, qRT-PCR, ELISA, confocal calcium imaging, and ultra-high-resolution transmission electron microscopy. The induced cells expressed key sensory neuron markers, including CGRP, PSD95, Synapsin, PRPH, TrkA, TrkB, TrkC, Ret, AnkyrinG, and Brn3a. Moreover, they displayed gene expression patterns associated with sensory neuron development, such as those of Avil, TrkA, Brn3a, Isl1, Runx3, and Shox2. Importantly, these cells exhibited calcium transients in response to KCl, BayK, and capsaicin stimulation. Capsaicin treatment also resulted in increased levels of CGRP and substance P, suggesting that the induced cells exhibit characteristics of mature neurons, including synaptic structures, functional calcium channels, and active signaling pathways. Our findings demonstrate that DRG-derived SGCs can be chemically induced to differentiate into sensory neuron-like cells, representing a novel approach for neuronal cell fate acquisition and a potential cell source for peripheral nerve repair.
Cytokines, central mediators of immune signaling, have emerged as pivotal regulators of neural stem cell (NSC) biology. Once regarded as immune-privileged, the central nervous system is now recognized as a dynamic site of immune-neural interaction, where meningeal and parenchymal immune cells modulate neurogenesis and brain plasticity through cytokine release. This review synthesizes current quantitative evidence on the effects of key cytokines including IL-6, FGF2, IL-15, IL-22, IL-10, and TNF-α on mouse NSCs studied exclusively in knockout models in vivo. This approach allows for a clearer understanding of their physiological roles, minimizing artefacts associated with in vitro systems, overexpression models, or inflammatory contexts, and focusing instead on their homeostatic functions. Collectively, these studies demonstrate that cytokine signaling profoundly influences NSC fate, proliferation, and differentiation. Importantly, by mapping cytokine expression within the dentate gyrus, the subventricular zone neurogenic niches, and the meninges, we put forward the provocative idea that brain borders are major sources of these factors, rather than the dentate gyrus itself. Understanding how immune-derived cues shape the NSC niche is critical for uncovering mechanisms underlying brain function, plasticity, and repair, with potential implications for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.
Organoids are three-dimensional cellular structures formed through the self-organization of stem cells that mimic the structure and function of in vivo organs, offering broad applications in biomedical research. Mesenchymal stem cells (MSCs) are multipotent cells characterized by their self-renewal capacity and versatile biological roles, particularly in immunomodulation and angiogenesis promotion. While literature suggests that MSCs play a pivotal role in organoid formation, the precise mechanisms underlying this phenomenon remain elusive. In this review, we systematically dissect the dual roles of MSCs in organoid construction, including their direct contributions as initiating cells and indirect effects via immunomodulation and angiogenesis, while highlighting unresolved mechanistic questions and future translational potential.
Despite our understanding of the musculoskeletal system under homeostatic conditions and during tissue remodeling, the interplay between muscle and bone development in response to gestational perturbations is less well understood. Here, we used the colony-stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 to disrupt macrophage and osteoclast proliferation, differentiation, and survival during the embryonic period in order to study the impacts on craniofacial development using high-resolution microcomputed tomography (μCT). Cranioskeletal and mandibular size and shape were assessed using geometric morphometric (GM) analysis and dense correspondence analysis (DeCA), while contrast-enhanced μCT and DeCA were utilized to examine the consequences of prenatal CSF1R inhibition on P1 offspring musculature. Combined, we observed significant disruptions to cranioskeletal and mandibular morphologies, and notable changes in the shape of the muscles of mastication and tongue in newly born pups exposed to the CSF1R inhibitor PLX5622 in utero . By assessing the craniofacial skeleton and associated musculature at birth, we provide a more direct view of how inhibition of CSF1R signaling across embryogenesis contributes to changes in musculoskeletal development during periods of craniofacial morphogenesis.
Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely associated with mitochondrial dysfunction. This study aimed to explore the role of myocyte enhancer factor 2A (MEF2A) in alleviating sarcopenia, focusing on its regulatory effect on mitochondrial homeostasis. AAV9-MEF2A was administered to 24-month-old male SAMP8 mice, and their endurance capacity and muscle histology were assessed. In vitro, MEF2A was overexpressed in C2C12 cells to examine its impact on myoblast proliferation and differentiation. Chromatin immunoprecipitation (ChIP), luciferase assays, and rescue experiments were conducted to identify downstream targets and validate the MEF2A-regulated signaling pathway. MEF2A overexpression significantly enhanced endurance performance, with a 1.17-fold increase in muscle mass, a 2.4 to 4.9-fold decrease in muscle atrophy markers compared to the AAV9-NC group, and a nearly 2 to 3-fold increase in mitochondrial biogenesis and antioxidant enzyme expression in aged mice. In C2C12 cells, MEF2A stimulated proliferation (1.8 fold increase in EdU-positive cells vs vector group) and differentiation (2 to 3-fold increase in differentiation markers vs vector group) while improving mitochondrial function through 1.5 to 2-fold increases in both OxPhos complex proteins and mitochondrial biogenesis genes compared to vector control. Mechanistically, MEF2A directly activated the PGC-1α/NRF2 axis, as validated by ChIP and reporter assays. Rescue experiments further verified the critical role of this pathway in MEF2A-mediated effects. These findings demonstrate that MEF2A mitigates sarcopenia by improving mitochondrial function and promoting muscle regeneration via activation of the PGC-1α/NRF2 signaling axis. MEF2A represents a promising therapeutic target for combating age-related muscle degeneration.
Following fertilization, there is an initial period of rapid cell division that leads to the formation of a multicellular structure known as the blastula, or blastocyst. Within this structure, sialic acids play a key role in influencing cellular processes such as signaling, cell-to-cell contact, and adhesion. In species that develop internally, the blastocyst undergoes implantation and placentation, which depend on maternal immunomodulation facilitated by sialylated proteins and enzymes involved in the biosynthesis of sialic acids. Although research has shown that the elimination of certain initial enzymes in the sialic acid synthetic pathway can lead to reduced embryonic viability, the precise role of these enzymes remains to be further investigated, particularly in the blastula of externally developing species, which have received limited attention. Recently developed blastoid models present promising prospects for future research in this field.
During primary neurulation in amniote embryos, the neural plate gives rise to the neural tube in a process requiring the coordination of forces at different scales throughout a geometrically complex tissue. The ways in which this process fails inform us of the complex mechanical conditions required for its correct completion. Previous results showed that the functional disruption of MARCKS, a protein which simultaneously interacts with the plasma membrane and actin filaments, resulted in neural tube closure defects with apical cell extrusion. Here, we demonstrate that this is an example of “live cell extrusion”, wherein extruded cells are not undergoing apoptosis. This suggests that extrusion in this case might be due to a mechanical instability in the neural plate. Using an expanded energy-based vertex model of pseudostratified epithelia we then show that extrusion may be elicited by a reduction in the relative surface tension of apical and basal interfaces with respect to cell-cell interfaces. Finally, by considering a continuum description of a simplified epithelium we derive an approximate quantitative threshold for single-layered epithelial stability in the form of a power law relating cell density to the relative value of interfacial surface tensions. Our work serves to explain an example of how alterations in polarization and forces at the single-cell level can produce tissue-scale instabilities which not only greatly alter its morphology but can also ultimately lead to severe developmental defects.
