Development最新文献

Dendritic cells (DCs) are key cellular components of the immune system and perform crucial functions in innate and acquired immunity. In mammals, it is generally believed that DCs originate exclusively from hematopoietic stem cells (HSCs). Using a temporal-spatial resolved fate-mapping system, here we show that, in zebrafish, DCs arise from two sources: dorsal aorta-born endothelium-derived hematopoietic progenitors (EHPs) and HSCs. The EHP-derived DCs emerge early, predominantly colonizing the developing thymus during larval stages and diminishing by juvenile stages. In contrast, HSC-derived DCs emerge later and can populate different tissues from late larval stages to adulthood. We further document that the EHP- and HSC-derived DCs display different dependencies on Fms-like tyrosine kinase 3 (Flt3), a pivotal receptor tyrosine kinase crucial for DC development in mammals. Our study reveals the presence of two distinct waves of DC development in zebrafish, each with unique origins and developmental controls.

The evolutionarily conserved Hox genes define segment identities along the anterior-posterior axis and are expressed in most cell types within each segment, performing specific functions tailored to cellular needs. It has been suggested previously that Drosophila adult flight muscles in the second thoracic segment (T2) develop without direct Hox gene input, relying instead on ectodermal signals to shape their identity. However, our research, leveraging single-cell transcriptomics of Drosophila wing discs and Hox perturbation experiments using CRISPR technology and gain-of-function assays, unveiled a more intricate regulatory landscape. We found that the Hox protein Antennapedia (Antp) is essential for adult flight muscle development, acting in two crucial ways: by regulating the cell cycle rate of adult muscle precursors (AMPs) through repression of proliferation genes, and by guiding flight muscle fate via regulation of Hedgehog (Hh) signalling during cell fate establishment. Antp, along with its co-factor Apterous (Ap), directly interacts with the patched (ptc) locus to control its expression in AMPs. These findings challenge the notion of T2 as a 'Hox-free' zone, highlighting the indispensable role of low-level Antp expression in adult muscle development.

Numerous regulators of cardiomyocyte (CM) proliferation have been identified, yet how they coordinate during cardiac development or regeneration is poorly understood. Here, we developed a computational model of the CM proliferation regulatory network to obtain key regulators and systems-level understanding. The model defines five modules (DNA replication, mitosis, cytokinesis, growth factor, Hippo pathway) and integrates them into a network of 72 nodes and 88 reactions that correctly predicts 74 of 81 (91.35%) independent experiments from the literature. The model predicts that in response to YAP activation, the Hippo module crosstalks to the growth factor module via PI3K and cMyc to drive cell cycle activity. This predicted YAP-cMyc axis is validated experimentally in rat CMs and further supported by YAP-stimulated cMyc open chromatin and mRNA in mouse hearts. This validated computational model predicts how individual regulators and modules coordinate to control CM proliferation.

Zebrafish have a high capacity to regenerate their hearts. Several studies have surveyed transcriptional enhancers to understand how gene expression is controlled during heart regeneration. We have identified REN (the runx1 enhancer) that, during regeneration, regulates the expression of the nearby runx1 gene. We show that runx1 mRNA is reduced with deletion of REN (ΔREN), and cardiomyocyte proliferation is enhanced in ΔREN mutants only during regeneration. Interestingly, in uninjured hearts, ΔREN mutants have reduced expression of adamts1, a nearby gene that encodes a Collagen protease. This results in excess Collagen within cardiac valves of uninjured hearts. The ΔREN Collagen phenotype is rescued by an allele with Δrunx1 mutations, suggesting that in uninjured hearts REN regulates adamts1 independently of runx1. Taken together, this suggests that REN is rewired from adamts1 in uninjured hearts to stimulate runx1 transcription during regeneration. Our data point to a previously unappreciated mechanism for gene regulation during zebrafish heart regeneration. We report that an enhancer is rewired from expression in a distal cardiac domain to activate a different gene in regenerating tissue.

Retinal ganglion cells (RGCs) are the projection neurons of the retina, and their death promotes an irreversible blindness. Several factors were described to control their genesis during retinal development which include Atoh7 as a major orchestrator for RGC program and downstream targets, including Pou4f factors, which in turn regulate key aspects of terminal differentiation. The absence of POU4F family genes results in defects in RGC differentiation, aberrant axonal elaboration and ultimately RGC death, confirming the requirement of POU4F factors for RGC development and survival, with a critical role in regulating RGC axon outgrowth and pathfinding. Here, we investigated in vivo whether ectopic Pou4f2 expression in late retinal progenitor cells (late RPCs) is sufficient to induce the generation of cells with RGC properties, including long range axon projections. We showed that Pou4f2 overexpression generates RGC-like cells that share morphological and transcriptional features with RGCs normally generated during early development and extend axonal projections up to the brain. In conclusion, these results showed that POU4F2 alone was sufficient to promote critical properties of projection neurons from retinal progenitors outside their developmental window.

Forty first-trimester human hearts were studied to lay groundwork for further studies of principles underlying congenital heart defects. We first sampled 49,227 cardiac nuclei from three fetuses at 8.6, 9.0, and 10.7 post-conceptional weeks (pcw) for single-nucleus RNA sequencing, enabling distinction of six classes comprising 21 cell types. Improved resolution led to identification of novel cardiomyocytes and minority autonomic and lymphatic endothelial transcriptomes, among others. After integration with 5-7 pcw heart single-cell RNAseq, we identified a human cardiomyofibroblast progenitor preceding diversification of cardiomyocyte and stromal lineages. Analysis of six Visium sections from two additional hearts was aided by deconvolution, and key spatial markers validated on sectioned and whole hearts in two- and three-dimensional space and over time. Altogether, anatomical-positional features including innervation, conduction and subdomains of the atrioventricular septum translate latent molecular identity into specialized cardiac functions. This atlas adds unprecedented spatial and temporal resolution to the characterization of human-specific aspects of early heart formation.

Land plants alternate between asexual sporophytes and sexual gametophytes. Unlike seed plants, ferns develop free-living gametophytes. Gametophytes of the model fern Ceratopteris exhibit two sex types: hermaphrodites with pluripotent meristems and males lacking meristems. In the absence of the pheromone antheridiogen, males convert to hermaphrodites by forming de novo meristems, although the mechanisms remain unclear. Using long-term time-lapse imaging and computational analyses, we captured male-to-hermaphrodite conversion at single-cell resolution and reconstructed the lineage and division atlas of newly formed meristems. Lineage tracing revealed that the de novo-formed meristem originates from a single non-antheridium cell: the meristem progenitor cell (MPC). During conversion, the MPC lineage showed increased mitotic activity, with marginal cells proliferating faster than inner cells. A mathematical model suggested that stochastic variation in cell division, combined with strong inhibitory signals from dividing marginal cells, is sufficient to explain gametophyte dynamics. Experimental disruption of division timing agreed with the model, showing that precise cell cycle progression is essential for MPC establishment and sex-type conversion. These findings reveal cellular mechanisms governing sex conversion and de novo meristem formation in land plants.

Aleksandra Pękowska leads the Dioscuri Center for Chromatin Biology and Epigenomics at the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw, Poland, where she studies the role of astrocytes in brain development. Her research connects astrocyte chromatin architecture to broader questions about how these glial cells have influenced human brain evolution. We met Aleksandra over Zoom to discuss her career path so far. She told us about how she came to work on nervous system development, the interdisciplinary nature of her research group, and how she almost ended up studying law at university.

Gynoecium patterning is dependent on the dynamic distribution of auxin, the signalling of which is transduced through several distinct pathways. ETTIN (ETT)-mediated signalling occurs independently of the canonical auxin pathway, and ETT shares partial redundancy with Auxin Response Factor 4 (ARF4) in the gynoecium. ETT and ARF4 were previously hypothesized to translate auxin gradients into patterns of tissue polarity alongside other ARFs. As ARF repressors, ETT/ARF were assumed to antagonistically regulate targets shared with ARF activators of the canonical pathway. Here, comparative transcriptomics identified the distinct and overlapping targets of ETT/ARF4 in the Arabidopsis gynoecium. However, ETT/ARF4 targets with known roles in gynoecium development did not conform to models of A-B ARF antagonism, leaving the relationship with the canonical pathway unclear. Mutants in tir1 afb2 ett were therefore generated in Arabidopsis and Capsella to assess the relationship between the two pathways, and their conservation in species with distinct fruit shapes. The data presented indicate conserved synergism between the two pathways in gynoecium development and suggest a role for ARF4 in the integration of these pathways in Brassicaceae with distinct fruit shapes.

Hematopoietic development is tightly regulated by various factors. The role of RNA m6A modification during fetal hematopoiesis, particularly in megakaryopoiesis, remains unclear. Here, we demonstrate that loss of m6A methyltransferase METTL3 induces formation of double-stranded RNAs (dsRNAs) and activates acute inflammation during fetal hematopoiesis in mouse. This dsRNA-mediated inflammation leads to acute megakaryopoiesis, which facilitates the generation of megakaryocyte progenitors but disrupts megakaryocyte maturation and platelet production. The inflammation and immune response activate the phosphorylation of STAT1 and IRF3, and upregulate downstream interferon-stimulated genes (ISGs). Inflammation inhibits the proliferation rate of hematopoietic progenitors and further skews the cell fate determination toward megakaryocytes rather than toward erythroid from megakaryocyte-erythroid progenitors (MEPs). Transcriptional-wide gene expression analysis identifies IGF1 as a major factor whose reduction is responsible for the inhibition of megakaryopoiesis and thrombopoiesis. Restoration of IGF1 with METTL3-deficient hematopoietic cells significantly increases megakaryocyte maturation. In summary, we elucidate that the loss of RNA m6A modification-induced acute inflammation activates acute megakaryopoiesis, but impairs its final maturation through the inhibition of IGF1 expression during fetal hematopoiesis.