Transcription involves initiation, pausing, elongation, and termination. Suppressor of Ty5 (SPT5) regulates promoter-proximal pausing and elongation, but how it orchestrates both steps during dynamic developmental changes in gene expression remains unclear. Here, using rapid optogenetic depletion in Drosophila embryos, we uncover different consequences of SPT5 removal at different developmental stages. In early embryos, SPT5 depletion causes a shift of RNA polymerase II (Pol II) from the canonical pausing site to the +1 nucleosome, which is strongly positioned. In late embryos, SPT5 depletion similarly reduces pausing at the canonical site, but the transcriptional machinery can overcome the +1 nucleosome—which appears more labile at this time point—moving into the gene body. This results in lethality and both up- and downregulation of expression, depending on the balance between Pol II entering the gene body and defective elongation. This is intensified for genes naturally increasing or decreasing their expression, indicating that SPT5 contributes to fine-tuning dynamic expression changes.
In flowering plants (angiosperms), the Polygonum-type embryo sac accounts for approximately 70% of the female gametophytes. It contains three antipodal cells, one central cell, one egg cell, and two synergid cells. Apart from the female gamete cells, the synergid cells play a key role in sexual reproduction. This review traces the origin and research history of synergid cells and summarizes the latest research progress in understanding their core functions in the angiosperm-specific siphonogamy. In particular, we discuss the diverse functions of synergid cells in pollen tube guidance, pollen tube reception, and fertilization recovery. We highlight how angiosperms guarantee fertility by regulating the timing and sequence of the synergid cell degeneration and persistence. Moreover, we discuss important unresolved scientific questions in synergid cell research and provide an outlook on future research directions.
Salt stress severely limits rice productivity, yet the genetic basis of natural variation and the underlying mechanism remain poorly understood. Here, through genome-wide association analysis and fine-mapping, we identify a major quantitative trait locus (QTL) gene, Tolerance to Salt 1 (TOLS1), that negatively regulates salt tolerance in rice. Overexpression of TOLS1 increases salt sensitivity, whereas loss of function enhances salt tolerance. TOLS1 interacts with the small guanosine triphosphatase (GTPase) OsRacB and enhances its GTPase activity, thereby attenuating salt-induced cytosolic Ca2+ elevation. We further identify a natural coding variation, SNP9 (+1018 A/G), in TOLS1 that contributes to functional divergence, with the TOLS1A allele exerting a stronger negative effect on salt tolerance than TOLS1G. Collectively, these findings reveal that natural variation in TOLS1 modulates OsRacB-Ca2+ signaling and thereby contributes to salt tolerance divergence in rice. This study provides mechanistic insight into how TOLS1 allelic variation regulates salt signaling and offers a potential target for molecular design breeding.
Intratumoral heterogeneity fuels cancer progression and therapy resistance, yet the cooperative mechanisms between distinct subclones remain poorly defined. Here, we uncover a tumor-promoting form of cell competition wherein malignant clones hijack interclonal Hedgehog (Hh) and Wnt signaling to convert competitive pressure into a pro-tumorigenic force. In Drosophila, we find that Pp1-87B depleted, RAS-mutant "loser" cells undergo Hh-mediated apoptosis while secreting Wingless (Wg). This paracrine Wg signal hyperactivate β-catenin in neighboring RAS "winner" clones, reprogramming them into invasive super-competitors. This mechanism is conserved in human pancreatic ductal adenocarcinoma (PDAC), where PPP1CA loss in KRAS-mutant cells induces analogous Hh-Wnt synergy, accelerating tumor growth in mouse xenograft models and correlating with clonal selection in patient specimens. Our study elucidates a paradoxical role for cell competition in intratumoral heterogeneity, where distinct tumor clones across species exploit conserved developmental signaling pathways to fuel malignancy. These findings establish interclonal communication as a critical driver of tumor ecosystem dynamics and identify Hh-Wnt crosstalk as a promising therapeutic vulnerability in heterogeneous cancers.
Invariant natural killer T (iNKT) cells are a subset of innate-like T lymphocytes that play important roles in immune responses. The mechanisms underlying the stage-specific development and differentiation of iNKT effector subsets are not fully elucidated. Here, using Zbtb16-Cre-driven conditional knockout mice, we found that conditional deletion of the E3 ligase Von Hippel-Lindau (VHL) resulted in impaired terminal maturation of iNKT cells and attenuated lineage specification of the iNKT2 and iNKT17 subsets. VHL deficiency disrupted iNKT cell-mediated tumor surveillance, thereby promoting B16F10 pulmonary metastasis. VHL ablation triggered hypoxia-inducible factor 1α (HIF1α) accumulation, which upregulated Bnip3 expression and caused aberrant reactive oxygen species (ROS) accumulation, thus driving apoptosis. HIF1α upregulation suppressed iNKT2 differentiation by impairing mitochondrial respiration, whereas HIF2α-mediated IL2RA-STAT5 signaling inhibited iNKT17 specification. Together, our work identifies the VHL-HIF axis as a fundamental determinant of iNKT cell differentiation and function, offering a mechanistic basis for harnessing iNKT cells in cancer immunotherapy.
The pace of embryonic development differs between mammalian species, yet the molecular basis for this remains unknown. By comparing protein dynamics in mouse and human neural progenitors (NPs), we show that protein turnover is faster in mouse NPs, driven by higher rates of protein synthesis and degradation. Human NPs exhibit longer protein half-lives, reduced proteasomal activity, and lower proteasome abundance. These differences persist in post-mitotic neurons and are also observed in the embryonic spinal cord in vivo. Pharmacological inhibition of proteasomal activity slows differentiation in mouse NPs. Conversely, enhancing proteasomal activity accelerates neuronal output in human NPs. Moreover, accelerating the degradation of the key transcriptional repressor IRX3 in mouse NPs speeds the activation of its target gene. Together, these results provide evidence that species-specific regulation of proteasome-mediated proteolysis influences the timing of neural development and suggest that evolutionary tuning of proteasomal activity contributes to differences in embryonic developmental pace.
Autophagy is commonly viewed as a cell-autonomous degradative process governed by intracellular metabolic and stress signals,1 but how autophagy is coordinated across tissues in multicellular organisms remains unclear. Zheng et al. 2 identify two parallel neuronal circuits that non-cell-autonomously regulate muscle autophagy in C. elegans, revealing an unexpected role for the nervous system in orchestrating peripheral autophagy.
Fertilization is not merely the fleeting union of a pair of gametes but a tightly orchestrated cascade of cellular events. In this issue of Developmental Cell, Skory et al. use high-resolution live imaging in mouse and human oocytes to reveal a series of coordinated events during fertilization.1.
In this issue of Developmental Cell, Ayad et al.1 show that mesoderm specification in human embryonic stem cells (hESCs) can be induced by mechanical strain in a Y654-β-catenin-dependent mechanotransduction purpose. This feature is conserved with mechanical induction of endomesoderm specification by gastrulation in metazoan representatives of other superphyla.
Inhaling cold air triggers adipose tissue thermogenesis. In this issue of Developmental Cell, Jiang et al. utilized the cold exposure to lung only (CELO) system to demonstrate that cold air activates lung club cells via TREK-1 potassium channels.1 Cold exposure closes TREK-1 channels, causing membrane depolarization, which increases irisin production and induces adipose thermogenesis.
Human embryonic development proceeds more slowly than in mice. The segmentation clock offers a tractable model for studying species-specific developmental tempo, as its oscillation period in human induced presomitic mesoderm (iPSM) cells is approximately twice that of mouse. While the core clock gene HES7 exhibits slower protein degradation in human cells, it remains unclear whether such cross-species differences in protein stability reflect a general principle. Here, we perform a dynamic stable isotope labeling of amino acids in cell culture (SILAC)-based proteomic analysis of ∼5,000 proteins in human and mouse iPSM, and we uncover a broad trend of slower protein degradation in human cells, regardless of subcellular localization or degradation pathways. Moreover, inhibition of glycolysis in mouse iPSM partially phenocopies the human protein stability profile, and modulation of protein stability alters the tempo of both the segmentation clock and cellular differentiation. Our findings establish protein stability, with systematic differences across species, as a key mediator linking metabolism to developmental tempo.
Early heart development involves heart tube elongation, looping, and axial patterning, yet these processes remain difficult to study experimentally. While pluripotent stem cell-derived heart organoids model cardiomyocyte differentiation, they do not recapitulate early morphogenetic events. Here, we generate elongating heart organoids (EHOs) from human induced pluripotent stem cells that undergo coordinated elongation and looping-like curvature, resembling early cardiac morphogenesis. EHOs establish a venous-to-arterial axis with spatially organized sinus venosus-like, atrial, and ventricular cardiomyocytes, and exhibit sequential propagation of contractile activity along this axis. Single-cell transcriptomics and trajectory analyses, together with pulse-labeling, support a model in which progressive incorporation of cardiac cells from proliferative splanchnic mesodermal cells at the venous pole drives elongation of the cardiac structure. Consistent with in vivo phenotypes, TBX5 deletion results in shortened EHOs with reduced looping-like curvature and irregular contractions. Together, EHOs provide a human in vitro system that enables investigation of early cardiac morphogenesis.
KRAS mutations are highly prevalent in pancreatic cancer and are critical for epithelial reprogramming during tumor initiation. In this issue of Developmental Cell, Grimont et al.1 demonstrate that the three most common KRAS mutations differentially activate downstream signaling pathways, resulting in distinct capacities to develop pancreatic pre-neoplastic lesions.
Circadian clocks enable plants to predict temperature changes and adapt to the living climate, known as temperature entrainment and temperature compensation (TC), with largely unrevealed mechanisms. Here, we proposed that the circadian component PRR9 (PSEUDO-RESPONSE REGULATOR 9) has evolved for thermal adaptation by acting as a hub factor in transmitting temperature input and maintaining TC. High temperature promotes PRR9 protein accumulation and triggers liquid-liquid phase separation, which not only directly inhibits the transcription level of CCA1 but also facilitates the recruitment of ALKBH9B to remove m6A installation and accelerates CCA1 mRNA degradation. Moreover, we proposed a phyB-PRR9 thermoregulatory module to transmit progressively rising temperature via temperature-dependent interacting compartment alteration that regulates the repressive phase and activity of PRR9. Our findings unmasked plants that possess intricate high-temperature sensing mechanisms for adaptation to warming climates, laying a foundation for engineering thermo-resilient crops.
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.
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.
Organs comprise diverse cell types originating from shared or distinct lineages. During embryogenesis, mesodermal Pax7+ progenitors give rise to skeletal muscle as well as non-muscle lineages like dermis and adipocytes. Here, we asked whether Pax7+ cells retain multipotency during early postnatal limb muscle growth. Lineage tracing in neonatal mice revealed unexpected early postnatal plasticity, yielding multiple non-myogenic lineages, including a previously unrecognized subpopulation of fibro-adipogenic progenitors, termed Pax7FAPs. Using mouse models, we demonstrated that Notch signaling primes neonatal Pax7+ cells toward a fibrogenic molecular identity, biasing their trajectory away from myogenesis. Long-term tracing confirmed that neonatally generated Pax7FAPs persist into adulthood. Furthermore, adult muscle injury triggered de novo generation of Pax7FAPs, which exhibited higher proliferative capacity than resident stromal cells. This postnatal Pax7+ multipotency reveals an additional cellular contribution to muscle development and regeneration.
Prolonged cold exposure over winter impacts plant growth and development, but its role beyond flowering regulation remains underexplored. In this study, we show that extended cold enhances regenerative capacity, promoting both callus formation and shoot regeneration in Arabidopsis. This enhancement is mediated by the cold-induced AP2/ERF transcription factors C-REPEAT/DRE-BINDING FACTOR 1 (CBF1), CBF2, and CBF3, which interact with the histone acetyltransferase (HAT) HISTONE ACETYLTRANSFERASE OF THE GNAT FAMILY 1 (HAG1). The CBFs recruit HAG1 to the loci of key regeneration regulators, such as WUSCHEL-RELATED HOMEOBOX 5 (WOX5), to promote their expression via histone acetylation. Our findings thus uncover an epigenetic mechanism by which prolonged cold primes plants for enhanced regeneration, highlighting how environmental cues influence developmental plasticity in plants.
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.
