Somitogenesis is controlled by the segmentation clock, a molecular oscillator that controls periodic gene expression in unsegmented mesoderm and is regulated by a negative feedback loop driven by Hes/Her transcriptional repressors. In zebrafish, Pnrc2 is required for decay of her1 transcripts and additional oscillatory gene transcripts. Despite accumulation of numerous mRNAs, including those encoding developmental regulators, overt embryonic phenotypes are absent in pnrc2 mutants. Our previous work suggested that accumulated mRNAs are not translated in pnrc2 mutants, although the underlying mechanism(s) was unknown. We show here that many overexpressed transcripts in pnrc2 mutants have shortened poly(A) tails and are disengaged from ribosomes, and that deadenylation inhibition leads to somite defects in pnrc2 mutants. Transcripts encoding the P-body-associated protein Ddx61 are overexpressed and engaged with ribosomes in pnrc2 mutants, leading to an increase in Ddx61 protein that may compensate for the negative effects of transcript accumulation. Co-depletion of Ddx61 and Ddx6 in pnrc2 mutants increases her1 accumulation and leads to pleiotropic defects. Together, our results show that multiple post-transcriptional mechanisms ensure proper translation when mRNA decay is inhibited.

The binary cell fate decision between neuroendocrine (NE) and club cell lineages is fundamental to lung development and epithelial homeostasis, yet the mechanisms that maintain these lineages remain incompletely understood. Here, we show that Hes1, a Notch target gene, maintains club cell identity by suppressing neuroendocrine differentiation. Lineage-tracing analyses revealed that Scgb1a1-expressing club cells give rise to NE cells following Hes1 loss during development and adulthood. Single-cell RNA sequencing of endogenous NE (eNE) cells and induced NE (iNE) cells generated by Hes1 loss uncovered substantial heterogeneity within the iNE populations and transitional cells expressing Notch-associated genes and keratins. Lineage tracing further showed that iNE cells integrate into neuroepithelial bodies (NEBs), and iNE cells reconstructed cell-cell communication networks that closely resemble those of eNE cells. These findings indicate that club cells, including Scgb1a1-positive club cell progenitors and mature club cells, retain latent potential to adopt an NE fate, which is normally suppressed by Hes1. Our results identify club cells as a previously unrecognized cellular source of NE cells and reveal a key mechanism that preserves epithelial lineage identity in the lung.

Cell fate determination is fundamental to development. In the Drosophila ovary, a 16-cell germline cyst forms in which two pro-oocytes arise; one of the pro-oocytes is selected as the oocyte, while the remaining 15 cells differentiate into nurse cells. Here, we identify Mini spindles (Msps), a Drosophila XMAP215-family microtubule polymerase, as a key regulator of oocyte fate specification. msps mRNA and Msps protein are enriched in the pro-oocytes prior to oocyte specification. Elimination of Msps prevents oocyte specification and disrupts the accumulation of the oocyte marker Orb, producing egg chambers with 16 nurse cells. Conversely, optogenetic recruitment of Msps increases microtubule polymerization and promotes Orb accumulation in nurse cells, suggesting that Msps activity is sufficient to initiate key molecular events associated with oocyte specification. Furthermore, Msps associates with the germline-specific organelles, the spectrosome and fusome, and becomes asymmetrically distributed, biasing the two pro-oocytes toward oocyte fate. We propose that an Msps-dynein feedback loop amplifies small initial differences between the two pro-oocytes to specify a single oocyte.

Hematopoietic stem and progenitor cells (HSPCs) are essential for differentiation into all blood cell types. In mammals, the interaction between HSPCs and the fetal liver niche during development is critical for stem cell maturation. Integrin alpha 4 (Itga4) on HSPCs and vascular cell adhesion molecule (Vcam1) on niche cells are critical for HSPC colonization of the fetal liver (FL). Itga4 and Vcam1 also function in the zebrafish equivalent of the FL, the caudal hematopoietic tissue (CHT), however, the specific niche cells that express Vcam1 remain unclear. Using multiple approaches, including fluorescent in situ hybridization, we found Vcam1 is expressed in endothelial cells (ECs) and mesenchymal stromal cells (MSCs), but not macrophages. Time-lapse live imaging of itga4 mutants showed the Itga4-Vcam1 axis is not required for guiding HSPCs into the CHT niche but is required for their retention. Our results show that Itga4 on HSPCs, and Vcam1 on ECs and MSCs, are involved in CHT niche retention.

Neil Vargesson is Professor of Developmental Biology at the University of Aberdeen, with particular expertise in angiogenesis during embryonic development and the impact of pharmaceutical drugs, such as thalidomide, that cause limb and embryonic differences. His advocacy, communication and advisory work around thalidomide embryopathy, Primodos and drug safety has supported affected patients and their families across the globe, as well as influencing government health policies worldwide. A Fellow of the Royal Society of Edinburgh since 2021, Neil is the recipient of the 2026 British Society for Developmental Biology Wolpert Medal, which is awarded in honour of the late Lewis Wolpert for extraordinary contributions to the communication and teaching of developmental biology in the UK. Published to coincide with Lewis's birthday on 19 October, the following interview is a conversation with Neil about what the Wolpert Medal means to him as Lewis's last PhD student, his ethos and advice for doing science communication, as well as his outlook on the future of drug safety.

During epithelial remodeling, tissues exhibit solid- or fluid-like properties depending on developmental constraints. In soft matter systems like foams and colloidal glasses, component size influences material mechanics. Here, we investigated how cell and nuclear size affect tissue mechanics. mh mutant embryos have epithelia with doubled cell densities, creating cells with altered 3D aspect ratios. Nuclear volumes scale non-linearly with cell volumes, adopting rounder shapes and reduced apical-basal heights, suggesting that stiff nuclei deform less than cell cortices. These compacted nuclei resemble a jammed state, reducing tissue fluidity and impairing extension movements. Interestingly, oscillatory amplitudes and frequencies in mh cells are comparable to control despite their reduced size, demonstrating an uncoupling between biochemical oscillation machinery and cell dimensions. Additionally, though planar-polarized magnitudes are dampened, the angular assignment of interfacial behaviors is preserved, suggesting that this planar informational system still operates with high fidelity despite reduced cell dimensions. Thus, these results indicate that development has fine-tuned epithelial dimensions to work at time-scales compatible with embryonic requirements.

Whilst many animals can regenerate lost or damaged tissues following injury, the mechanisms that allow them to identify which specific cell type needs to be regenerated remains unclear. To address this, Cecilia Pellegrini and Peter Reddien map out the response mechanisms to a multitude of different injuries in the planarian flatworm, demonstrating that a general 'bystander' response in areas near injury sites might be sufficient for robust regeneration without the need for precise identification of missing tissues. To learn more about this paper and the people behind it, we spoke to first author Cecilia Pellegrini and corresponding author Peter Reddien, Professor of Biology at the Massachusetts Institute of Technology, USA.

This article discusses the preprinted work of Tardivo et al. (2026, preprint). As a preprint, this work has not yet undergone peer review.

The enteric nervous system (ENS) is the main branch of the peripheral nervous system that innervates the gastrointestinal tract controlling vital functions. It arises during embryogenesis via migration, proliferation and differentiation of neural crest-derived ENS progenitors. Perturbation of these processes, caused by mutations in key signalling pathway components and transcription factors, prevents progenitor colonisation of the distal gut, causing aganglionic phenotypes and enteric neuropathies such as Hirschsprung (HSCR) disease. While animal models implicate Notch signalling in ENS specification, its role in human ENS progenitor cell fate decisions remains unclear. Here, we employ a human pluripotent stem cell-based model to show that Notch signalling is a key regulator of human ENS progenitor dynamics. Quantitative modelling of our in vitro data indicates that Notch inhibition accelerates progenitor differentiation without substantially altering neuronal versus glial lineage bias. Furthermore, we establish that Notch signalling controls human ENS progenitor migration by influencing migration velocity and directionality. Together, these findings provide mechanistic insights into how Notch signalling disruption may contribute to the pathogenesis of human intestinal aganglionosis.

In mammals, the first cell fate decisions segregate pluripotent fetal cells from the differentiating extraembryonic lineages. In mouse, pluripotent progenitors can be identified as early as the 16-cell (morula) stage, based on their restricted expression of SOX2. In spite of the unique SOX2 expression pattern, however, the first cell fate decision proceeds normally in the absence of Sox2, suggesting an undiscovered compensatory mechanism. We have discovered that the closely related SOX paralogue Sox21 is expressed alongside, and independently of, Sox2 prior to blastocyst formation. Mouse embryos lacking both Sox2 and Sox21 exhibit a phenotype more severe than those lacking either gene alone, arresting during the morula-to-blastocyst transition. In fact, embryos lacking any three copies of Sox2 or Sox21 frequently phenocopy double knockouts, consistent with a dose-dependent genetic interaction. Finally, we have discovered the mechanism promoting parallel expression of Sox2 and Sox21. We show that, like Sox2, expression of Sox21 depends on TFAP2C, and not NANOG or OCT4, clarifying gene regulatory mechanisms preceding blastocyst formation. Overall, our study reveals a new SOX-dependent pathway regulating embryonic processes even earlier than previously appreciated.

Temporal patterning of retinal progenitor cells governs the sequential generation of retinal cell types, with gliogenesis occurring late in development. Sox8 and Sox9, members of the SoxE transcription factor family, are highly expressed in late-stage retinal progenitor cells and mature Müller glia, yet their functional roles remain incompletely defined. Here, we have employed gain- and loss-of-function approaches, single-cell multiomic profiling, and injury models to investigate Sox8 and Sox9 function. Overexpression of human SOX8 and SOX9 in early-stage mouse retinal progenitor cells both suppressed generation of early-born cells, consistent with a role in late-stage temporal identity, and induced ectopic generation of oligodendrocyte lineage-like cells. Conversely, conditional deletion of Sox8 and/or Sox9 in late-stage progenitors did not impair Müller glia specification, but caused radial displacement of glial nuclei into the outer retina and reduced expression of multiple markers of mature Müller glia. Loss of Sox8 and/or Sox9 in mature Müller glia modestly increased proliferation post-injury without inducing neurogenic competence. These findings suggest that Sox8 and Sox9 are dispensable for gliogenesis and repression of neurogenic competence, but are essential for proper laminar positioning and full terminal differentiation of retinal Müller glia.

In the female reproductive tract, species-specific progenitor populations in the cervix - stratified squamous progenitors in mice and columnar progenitors in humans - generate similar secretory epithelial subtypes with conserved functions. In their work, Mala Mahendroo and colleagues reveal the cellular origins of mucus-producing goblet cells by identifying olfactomedin 4 (Olfm4) as a progenitor lineage marker for goblet cells in the mouse cervix and vagina. To learn more about their work, we talked to the first author, Shanmugapriyaa Madhukaran, as well as the corresponding author, Mala Mahendroo, Professor of Obstetrics and Gynaecology, UT Southwestern Medical Center, USA.

This article discusses the preprinted work of Palumaa and colleagues (2026 preprint) as well as that of Li and team (2026 preprint). As preprints, these works have not yet undergone peer review.

Behavioral diversification can arise through evolutionary and inter-individual differences in neural circuit development. In the mushroom body, which is an associative learning center of arthropods, the number of Kenyon cells (KCs) varies across species and among individuals. How such variation is developmentally accommodated by projection neurons (PNs), which provide sensory input to KCs, is not understood. In Drosophila melanogaster, we have previously demonstrated that PNs scale their presynaptic bouton number to KC population size. Here, we identify developmental mechanisms underlying this input flexibility. Boutons form on axonal collaterals; for PNs, we find that collateral number is subtype specific and serves as a substrate through which bouton number scales to KC population size. Independent of PN identity or KC number, most individual collaterals produce only one to three boutons, suggesting collaterals are modular cell biological bouton units. Developing PNs initially overproduce nascent collaterals in the early pupa. The set of nascent collaterals that form boutons and mature is conditional on KC number, thereby executing scaling. Finally, early boutons bear filopodia that contact neighboring PN processes, suggesting that bouton-bouton interactions contribute to shaping these structures.

The ability to regenerate complex appendages varies strikingly across vertebrates, yet the developmental principles that enable complete limb regeneration remain incompletely understood. In mammals, regenerative responses are largely restricted to distal digit tips, whereas amphibians - such as the axolotl - can regenerate entire limbs throughout adulthood. This contrast provides a powerful framework for dissecting how adult tissues rebuild form, pattern and proportion after injury. In this Review, we synthesize recent advances from mammalian digit tip regeneration models and amphibian limb regeneration to examine core challenges of regeneration, including the establishment of regeneration-permissive niches, endogenous reprogramming of adult cells into regeneration-competent progenitors, integration of positional information across limb axes, and regulation of growth and scale. We highlight how comparative and functional studies are revealing conserved developmental programs that support regeneration, as well as key constraints that limit their engagement in mammalian limbs. Rather than serving as a template to be replicated in mammals, the amphibian limb provides a blueprint for understanding whether and how developmental programs can be reactivated (or replaced) in adulthood and why they fail to be fully engaged in mammalian limb injuries.