The endoplasmic reticulum (ER) is a critical quality-control organelle for protein homeostasis within the cell. The accumulation of misfolded or unfolded proteins triggers ER stress, which can be alleviated through the unfolded protein response (UPR) and ER phagy. These processes work in concert to preserve ER homeostasis, yet the molecular interactions between them remain poorly understood in plants. In this study, we identify the ER-anchored transcription factor NAC089 as an ER-phagy receptor acting downstream of the ADP-ribosylation factor (ARF)-like (ARL) GTPase ARLA1A under carbon starvation. Furthermore, we demonstrate that active ARLA1A inhibits ER phagy by negatively regulating NAC089. Notably, the ARLA1A-NAC089 axis coordinates ER phagy with the UPR to balance cell survival and death. Our findings unveil a multi-layered regulatory network that is essential for maintaining cellular homeostasis and enhancing plant adaptation to environmental stresses.

Mammalian embryonic diapause is a reversible state of pre-implantation dormancy characterized by metabolic rewiring toward lipid usage as energy source. Whether active signaling sustains this dormant state remained unclear. Here, we show that the transforming growth factor- β (TGF-β) pathway, previously thought to only be required post-implantation, is essential for diapause. Nodal signaling is activated and its downstream effector SMAD family member 2 (Smad2) is required during diapause in vivo. Using ex vivo blastocyst and embryonic stem cells models of diapause, we show that Smad2 represses peroxisome proliferator-activated receptor gamma (Pparg), a master regulator of lipid storage. Loss of Smad2-mediated Pparg repression leads to lipid accumulation and is incompatible with pausing. Our findings establish a Nodal-Smad2-Pparg axis that is pivotal for sustaining the transcriptional and metabolic programs of embryonic diapause. This axis may be redeployed in other contexts, including cancer dormancy and metabolic disorders.

Oxygen availability is crucial for embryonic development, influencing cellular metabolism and signaling within the embryo. Fluctuations in oxygen tension disrupt the equilibrium between glycolysis and mitochondrial respiration, leading to localized alterations in reactive oxygen species (ROS) production. At physiological levels, ROS, particularly hydrogen peroxide (H2O2), act as important signaling molecules. They actively modulate cellular processes through reversible oxidation of critical cysteine residues in redox-sensitive proteins, thereby fine-tuning the activities of various signaling pathways, transcription factors, and epigenetic regulators. Despite limited studies directly investigating ROS signaling in development, substantial literature suggests that many developmental pathways are influenced by ROS. This review aims to synthesize this existing evidence, explore the molecular mechanisms of thiol-dependent regulation, and examine how disruptions in redox balance impact cell fate decisions, developmental timing, and tissue morphogenesis. Our goal is to catalyze further research in this promising yet heavily underexplored area, highlighting its significance and timeliness.

Cold exposure is a well-known trigger for thermogenesis, primarily through skin cold-sensitive neurons activating adipose metabolism via the central nervous system (CNS). However, whether the lungs-also exposed to cold air-function as a cold sensor and regulate metabolism remains unknown. Here, using CC10-Cre- and adeno-associated virus (AAV)-based mouse models, we uncover a pulmonary cold sensing system that drives thermogenesis, establishing a peripheral thermoregulatory mechanism. Specifically, we identify KCNK2 channels in Club cells within the bronchial epithelium as primary pulmonary cold sensors, where cold exposure enhances Irisin expression and secretion via Ca[2+] fluctuations to drive thermogenesis in adipose tissue. Notably, pharmacological activation of this pathway via fluoxetine tracheal infusion enhances thermogenesis and ameliorates obesity in mice, highlighting a potential anti-obesity delivery strategy.

Roots, composed of diverse cell types across longitudinal developmental zones, are vital for plant survival against microbial challenges. Leveraging single-cell transcriptomics and live-cell imaging of Arabidopsis roots, we reveal here that plant-derived phytocytokines elicit more potent immune responses than microbe-derived patterns across root cell types and zones. The differential expression of receptors and key signaling modules in distinct cell types and zones contributes to the response intensity to specific elicitors. Phytocytokines sustain growth-defense trade-offs by suppressing the expression of receptor-like kinase genes associated with root cell division and elongation. The intensity of immune responses in different root zones is associated with fungal and bacterial pathogen invasion sites. Furthermore, motif-informed network inference highlighted key transcriptional regulators driving cell identity-specific transcriptomic immune responses. Our study provides a comprehensive landscape of transcriptional responses in plant roots in response to diverse immune elicitors, highlighting how distinct phytocytokines orchestrate stage- and cell type-dependent transcriptional reprogramming.

Epithelial cells sense and respond to mechanical forces by reinforcing connections between adherens junctions and the actin cytoskeleton. Tricellular junctions are key sites of mechanotransduction in epithelial cells, but how force responses are coordinated at these structures during epithelial remodeling is poorly understood. We show that the actin crosslinking protein Fimbrin is recruited by forces to tricellular junctions in Drosophila and promotes actin reorganization and cell adhesion during epithelial remodeling. In the absence of Fimbrin, cells fail to reorganize actin or recruit junction-stabilizing proteins to tricellular junctions under tension, disrupting cell adhesion. Conversely, increasing Fimbrin activity constitutively activates multiple force-response pathways, aberrantly stabilizing adhesion. We show that Fimbrin directs force responses by amplifying actomyosin contractility, and that force-regulated actin remodeling and Plastin3 and Afadin localization occur at tricellular junctions in the mouse embryo. These results suggest that conserved mechanisms underlie force responses at tricellular junctions in fly and mouse epithelia.

Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant Kras in the formation of pancreatic ductal adenocarcinoma. How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement Ptf1a-tdTomato mice and multiple KRAS mutants across several genetic, pharmacologic, and inflammatory perturbations in vivo. Whereas KRAS[G12D] co-opts injury to enable lineage reversion, enhancer reprogramming, and tumor initiation, KRAS[G12R/V] cannot sustain dedifferentiated and neoplastic transcriptional and epigenetic programs. Specifically, KRAS[G12R/V] mutants fail to invoke robust EGFR, AKT, and RAC1/VAV1 signaling and to license Pou2f3 and Vav1 in chromatin, such that only constitutive AKT activation is sufficient to rescue the tumorigenic potential of KRAS[G12R]in vivo. As the marked heterogeneity among KRAS variants begins early in tumorigenesis, these data are crucial to deciphering mutation-specific oncogenic trajectories and directing the implementation of KRAS-directed therapeutics.

Fertilization involves dynamic sperm-egg interactions, yet has been primarily studied in static samples. Here, we use high-resolution live imaging to capture fertilization from the moment of sperm binding in zona-intact mouse oocytes. We identify two phases of sperm remodeling: a static phase, during which sperm remain beneath the oocyte cortex as DNA decondensation and histone loading occur, and a mobile phase characterized by stereotyped sperm movement. Initial displacement away from the spindle is driven by cytoplasmic streaming, with manipulations in mouse indicating that sperm movement requires chromatin decondensation and oocyte polarization. Subsequently, polar body cytokinesis generates convergent cortical flows that draw sperm toward the emerging female pronucleus. Finally, we capture sperm-egg fusion in human oocytes and characterize post-fusion events including meiotic resumption and sperm movement, offering a live-imaging description of human fertilization dynamics. Together, these findings provide a continuous spatiotemporal framework for mammalian fertilization, extended by initial observations in human oocytes.

The role of morphogenetic forces in cell fate specification is an area of intense interest. Using an ectopically expressed nonphosphorylatable mutant of β-catenin (Y654F) in human embryonic stem cell colonies, we provide evidence that impeding tension-dependent Src-mediated β-catenin phosphorylation compromises BMP4-driven Brachyury (T) expression. This impediment also disrupts the epithelial-to-mesenchymal transition essential for mesoderm specification. Mechanistically, the Y654F mutation prevents the translocation of the junctional and cytoskeletal pool of β-catenin to the nucleus. However, saturation of Wnt signaling with exogenous Wnt3a or the inhibition of GSK3β rescues mesoderm expression. These findings suggest that BMP4 initiates a force-dependent junctional β-catenin translocation upstream of both Wnt secretion and cytosolic Wnt/β-catenin stabilization to drive mesoderm specification. Ultimately, our work highlights the importance of force-dependent Wnt/β-catenin signaling in the self-organization of tissues during developmental processes, such as gastrulation, and emphasizes a role for fine-tuned molecular regulation of the Wnt signaling pathway.

RNA modifications constitute a dynamic layer of gene regulation during development. Among them, noncanonical caps, N[6]-methyladenosine (m[6]A), and pseudouridine (Ψ) represent three major classes of chemical marks. Noncanonical caps diversify the 5' end of RNA, whereas m[6]A and Ψ act as internal modifications that modulate RNA structure and RNA-protein interactions. Through these molecular effects, noncanonical caps, m[6]A, and Ψ influence RNA processing, localization, and function, thereby governing RNA fate in response to developmental and environmental cues. Advances in detection, quantification, and transcriptome-wide profiling have greatly expanded our understanding of these modifications, while revealing important technical challenges. In this review, we discuss how these three major RNA modifications regulate developmental programs in plants and animals, with emphasis on their molecular mechanisms and biological functions. We further highlight their potential relevance for therapeutic strategies in human diseases and agricultural approaches for crop improvement under climate change.

Plants maintain active stem cell populations throughout their lives, yet these systems are remarkably resilient to genetic, environmental, and mechanical perturbations. Synthesizing evidence from the shoot apical meristem, root apical meristem, and vascular cambium of Arabidopsis thaliana, we argue that this robustness is not primarily a consequence of genetic redundancy but an emergent property of distributed regulatory architectures. Multiple mechanisms contribute distinct buffering layers to plant stem cell systems, including negative feedback loops, mobile transcription factors, antagonistic hormonal fields, mechanical constraints, chromatin-level noise filtering, and regenerative self-organization. Across all three major plant stem cell systems, cell identity is imposed by position rather than lineage, and fast environmental responses are temporally decoupled from slow patterning dynamics. We propose that these recurring design principles underlying plant stem cell systems constitute a conserved and evolvable toolkit that enables indeterminate plant growth.

Over the past ∼25 years, our understanding of neural circuit development in the central nervous system has shifted. Once considered passive supporters, glial cells, namely, astrocytes, oligodendrocyte lineage cells, and microglia, are increasingly recognized as active regulators of developmental circuit formation and maturation. In this review, we synthesize evidence for the multifaceted functions by which glial cells instruct neuronal circuit establishment and maturation across developmental stages and in both vertebrate and invertebrate nervous systems. We describe the programs deployed to guide successive phases of synapse formation, refinement, plasticity, and stabilization in a circuit- and experience-dependent manner. We also highlight how an extensive glia-glia communication repertoire provides another critical layer of control over development. In summary, glia cooperatively shape circuit development by instructing, stabilizing, or eliminating specific wiring programs. Disruption of this coordinated logic, beyond dysfunction of any single glial or neuronal process, underlies vulnerability to neurodevelopmental and neuropsychiatric disease.

Cancers are complex cellular communities comprising tumor cells and their microenvironment. Recent advances in cancer biology have emerged from efforts to analyze tumors as tissues, in which emergent properties arise as tumor cells interact with one another, their microenvironment, and the host tissue. In this review, we consider interactions involving mechanical forces and mechanosignaling pathways that detect changes in physical inputs to regulate cellular behavior. This rapidly developing field provides perspectives for understanding cancer biology and tumor interactions with the host ecosystem.

Spatial technologies have revolutionized the study of human development by enabling molecular profiling within intact tissue architecture. Advances in spatial transcriptomics, epigenomics, proteomics, metabolomics, and multiomics have generated high-resolution atlases of embryonic and fetal organs, which have revealed how gene regulatory programs, cell-cell interactions, and tissue patterning are organized in space and time during organogenesis. However, limited access to human developmental tissues and ethical constraints restrict experimental validation and mechanistic studies. Stem cell-derived organoids offer tractable, human-relevant models that recapitulate key structural and cellular features of developing organs while allowing controlled perturbation and longitudinal analysis. Integrating spatial profiling with organoids constitutes a sophisticated methodology for systematic analysis of lineage specification, niche signaling, and metabolic maturation. This review synthesizes current spatial technologies, highlights emerging organoid-based technologies, and discusses future directions integrating spatial multiomics, machine learning, and accessible data resources to advance mechanistic and predictive developmental biology.

Stem cell-derived embryo models help to transform inaccessible stages of mammalian development into experimentally tractable systems, revealing how development succeeds, stalls, or fails under defined conditions. Because natural embryos are shaped by stringent in vivo selection, they conceal many trajectories that embryo models bring into view. In mouse and human systems, embryo-like structures emerge through shared morphogenetic transitions-cell sorting, polarization, lumen formation, and symmetry breaking-with variable efficiency and along multiple routes. These alternative trajectories expose the rules and constraints of self-organization, the roles of extra-embryonic tissues, and the parameters that stabilize robust development. We propose that embryo models can be understood as experiments in productive failure, in which divergence from in vivo development becomes mechanistically informative. In doing so, embryo models reveal the hidden grammar of development, expose the fragilities that underlie pregnancy loss, and potentially reshape what is possible for regenerative biology and bioengineering.