Development最新文献

Organ development relies on interactions among different cell types that form three-dimensional structures to carry out specific tasks. This process often involves active migration of progenitor cells toward specific positions within the embryo, where the cells then become immotile and form stable connections among themselves and with neighboring cells. In this work, we study the process of motility loss using zebrafish primordial germ cells as an in vivo model. We show that changes in embryonic tissues as well as cell-autonomous events regulate germ cells' behavior as they arrive at their target region. Importantly, we find that reduction in germ cell motility is correlated with the decay of RNA encoding for Dead end 1 (Dnd1), a conserved vertebrate RNA-binding protein that is essential for PGC migration. Indeed, decreasing or increasing the level of Dnd1 results in a premature or delayed stop to motility, respectively. These findings represent an RNA decay-based mechanism for timing the duration of cell migration in vivo.

Tissue boundaries pattern embryos, suppress tumours, and provide directional cues. Tissue boundaries are associated with supracellular cables formed by actin and the molecular motor non-muscle myosin II. Actomyosin cables generate tension that prevents cell mixing. Whether other cellular behaviours contribute to the formation of linear interfaces between cell populations remains unclear. In the Drosophila embryo, an actomyosin-based boundary separates the ectoderm from the mesectoderm, a group of neuronal and glial progenitors. Mathematical modelling predicted that cell divisions in the ectoderm challenge the mesectoderm-ectoderm (ME) boundary. Consistent with this, suppressing ectoderm cell divisions in vivo prevented cell mixing across the ME boundary when actomyosin-based tension was lost. Our mathematical model also predicted that cell divisions sharpen the ME boundary by reducing tension and increasing cell motility in the ectoderm. We found that inhibiting ectoderm divisions in vivo reduced boundary linearity. Using laser ablation and cell tracking, we demonstrated that cell divisions reduced junctional tension and increased cell movement in the ectoderm. Together, our results reveal that cell divisions facilitate cellular rearrangements to increase fluidity in a novel mechanism for boundary refinement.

Developing populations of connected neurons often share spatial and/or temporal features that anticipate their assembly. A unifying spatiotemporal motif might link sensory, central, and motor populations that comprise an entire circuit. In the sensorimotor reflex circuit that stabilizes vertebrate gaze, central and motor partners are paired in time (birthdate) and space (dorso-ventral). To determine if birthdate and/or dorso-ventral organization could align the entire circuit, we measured the spatial and temporal development of the sensory circuit node: the vestibular ganglion neurons. We discovered that progressive dorsal-to-ventral organization closely predicts vestibular ganglion development, with additional organization along its functional (rostrocaudal) axis. With an acute optical lesion and calcium imaging paradigm, we found that this common temporal axis anticipated functional sensory-to-central partner matching. We propose a "first-come, first-served" model in which birthdate organizes and assembles the sensory, central, and motor populations that comprise the gaze stabilization circuit, a general strategy for poly-synaptic circuit assembly across embryonically-diverse neural populations.

During perinatal development, liver metabolism is tightly regulated to ensure energy supply for the newborn. Before birth, glycogen is stored in hepatocytes and later metabolized to glucose, meeting neonatal energy demands. Shortly after birth, lipogenesis begins, driven by transcriptional activation of enzymes involved in fatty acid oxidation. These processes are thought to be largely regulated by systemic insulin and glucagon levels. However, the role of liver-derived local factors in neonatal hepatocyte metabolism remains unexplored. Kupffer cells (KCs), the liver's resident macrophages, colonize the fetal liver early in embryogenesis and support liver metabolism in adulthood. Yet whether KCs influence neonatal hepatocyte metabolism is unknown. Using conditional knockout mouse models targeting macrophages, we demonstrate that yolk sac-derived KCs play a crucial role in hepatocyte glycogen storage and function by regulating the tricarboxylic acid cycle, a role monocyte-derived KC-like cells cannot substitute. Newborn pups lacking yolk sac-derived KCs mobilize glycogen more rapidly, a process in part regulated by insulin-like growth factor 1 (Igf1) production. Our findings identify KCs as major source of Igf1, with local production essential for balanced hepatocyte metabolism at birth.

Whereas ligaments hold skeletal elements together, tendons bridge the musculature with the skeleton. How connective tissues of the right type and function are specified in distinct regions of the developing body remains unclear. Here, we have generated single-cell datasets of RNA expression and chromatin accessibility for scxa:mCherry+ connective tissues of the developing zebrafish face. We identified cell clusters corresponding to tendon, ligament, periligament, perichondrium and other types, as well as tendon and ligament subtypes with an osteogenic signature that may explain the remodeling of ligament-bone interfaces and the formation of sesamoid bones. We further identified several enhancers driving spatially restricted transgenic activity in ligaments, periligament tissue and other connective tissues. By utilizing a ligament-specific photoconvertible nlsEOS transgenic line, we revealed directional growth of ligaments. In addition, we found that nkx3.2 is expressed within the joint-proximal domain of the major jaw-stabilizing ligament, with this domain being lost in nkx3.2 mutants. Our study reveals distinct gene regulatory programs for jaw connective tissue diversification and provides a mechanism underlying the propensity of tendons and ligaments to ossify in normal and pathological contexts.

Spatial regulation of Notch signaling is crucial for tissue patterning, yet how compartment-specific activation thresholds are set remains unclear. Here, we identify Kuzbanian (Kuz) expression as a key spatially controlled determinant in the Drosophila midgut. Kuz is suppressed in the copper cell region by BMP signaling and induced by EGFR activity in adjacent compartments, directly explaining regional differences in Notch activation. Strikingly, elevated Kuz expression alone is sufficient to cleave Notch and trigger ligand-independent signaling. cis-Delta potently inhibits this non-canonical activation, establishing it as a key safeguard. Furthermore, high Kuz levels enable trans-Delta ligands on neighboring cells to overcome cis-inhibition. These findings support a model in which spatially defined Kuz expression sets a proteolytic threshold that determines the outcome of competition between cis-inhibition and trans-activation. Our findings reposition Kuz/ADAM10 as a crucial spatial regulator of Notch signaling, providing a new framework for understanding signal integration in vivo.

The intestinal interphase is where epithelial renewal and tissue maintenance are balanced alongside immunological regulation. How these functions integrate with cellular signalling is under investigation. Here, we studied the role of the evolutionarily conserved innate immune Toll/NF-κB pathway in Drosophila intestinal regeneration. We found that the core components of the canonical Toll pathway were necessary for intestinal stem cell (ISC) mitosis in homeostasis and upon infection. Toll activation was sufficient to push ISCs into mitosis and the enteroblast (EB) fate, but blocked EB differentiation resulting in ISC and EB accumulation. This was mediated by JNK and Akt/TOR signalling. When JNKK, JNK, Akt or TOR activity was reduced in gut progenitors, ISC mitosis was suppressed. Toll activation also triggered suppression of antimicrobial lysozyme and amidase genes, which led to increased gut bacterial density. Our results identify Toll as necessary and sufficient for ISC mitosis. Our model is that the Toll pathway acts as a regulator of the intestinal landscape integrating JNK and Akt signals to achieve gut tissue renewal and control of commensal bacteria density.

Cellular plasticity, the ability of a differentiated cell to adopt another phenotypic identity, is restricted under basal conditions, but can be elicited upon damage. However, the molecular mechanism enabling such plasticity remains largely unexplored. Here, we report damage-induced cellular plasticity of secretory enteroendocrine cells (EEs) in the adult Drosophila midgut. Ionizing radiation induces EE fate conversion and activates stress-responsive programs in EE lineages, accompanied by the induction of the stress-inducible transcription factor Xrp1 and the cytokine gene upd3. Xrp1 and upd3 are both necessary for radiation-induced EE plasticity. Under basal conditions, EE-specific Xrp1 overexpression triggers ectopic expression of progenitor-specific genes, which is necessary for Xrp1 to drive EE plasticity. Our work identifies Xrp1 as a crucial regulator that coordinates damage-induced signaling and transcriptional reprogramming, enabling the reactivation of cellular plasticity in differentiated cells.

During periods of starvation, some organs and tissues are selectively spared. A recent study in Development shows that microbiome-dependent intestinal sparing in Drosophila is coordinated by the hormone ecdysone. To learn more about this work, we spoke to first author Longwei Bai and corresponding author François Leulier, Director and Group Leader at Institut de Génomique Fonctionnelle de Lyon, France.

Wdr5, a multifunctional scaffolding protein, with established roles in chromatin regulation and pluripotency, but its functions in early development remain poorly understood. Here, we show that Xenopus wdr5 is expressed in blastula stem cells and enriched in neural crest cells. Depletion of wdr5 abolished neural crest gene expression in embryos and in reprogrammed explants while expanding neural plate border and neural plate domains. Gain-of-function experiments revealed striking dose-dependent effects: low Wdr5 enhanced neural crest formation, whereas high levels suppressed it, suggesting a requirement for precise stoichiometry with interacting partners. We identify Myc as an essential co-factor for Wdr5 in neural crest - Wdr5 and Myc physically interact and co-expression at defined ratios rescues neural crest formation. We further show that the Wdr5 WBM site is required for Myc-dependent activation of neural crest genes, whereas the WIN site regulates myc expression itself; both domains are necessary to rescue wdr5 depletion. These findings reveal that Wdr5 orchestrates neural crest development through multiple, domain-specific mechanisms, integrating stoichiometric control with partner-specific transcriptional regulation, and underscores the importance of precise co-factor ratios in cell fate decisions.