Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 89,516 bioRxiv papers from 383,511 authors.
Most downloaded bioRxiv papers, all time
in category developmental biology
2,613 results found. For more information, click each entry to expand.
96,194 downloads developmental biology
Steve Horvath, Kavita Singh, Ken Raj, Shraddha Khairnar, Akshay Sanghavi, Agnivesh Shrivastava, Joseph A. Zoller, Caesar Z Li, Claudia B. Herenu, Martina Canatelli-Mallat, Marianne Lehmann, Leah C. Solberg Woods, Angel Garcia Martinez, Tengfei Wang, Priscila Chiavellini, Andrew J. Levine, Hao Chen, Rodolfo G Goya, Harold L Katcher
Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging. ### Competing Interest Statement Several authors are founders, owners, employees (Harold Katcher and Akshay Sanghavi) or consultants of Nugenics Research (Steve Horvath and Agnivesh Shrivastava) which plans to commercialize the "Elixir" treatment. Other authors (Kavita Singh, Shraddha Khairnar) received financial support from Nugenics Research. The other authors do not have conflict of interest.
8,656 downloads developmental biology
During development, forces transmitted between cells are critical for sculpting epithelial tissues. Actomyosin contractility in the middle of the cell apex (medioapical) can change cell shape (e.g., apical constriction), but can also result in force transmission between cells via attachments to adherens junctions. How actomyosin networks maintain attachments to adherens junctions under tension is poorly understood. Here, we discovered that microtubules promote actomyosin intercellular attachments in epithelia during Drosophila mesoderm invagination. First, we used live imaging to show a novel arrangement of the microtubule cytoskeleton during apical constriction: medioapical Patronin (CAMSAP) foci formed by actomyosin contraction organized an apical non-centrosomal microtubule network. Microtubules were required for mesoderm invagination but were not necessary for initiating apical contractility or adherens junction assembly. Instead, microtubules promoted connections between medioapical actomyosin and adherens junctions. These results delineate a role for coordination between actin and microtubule cytoskeletal systems in intercellular force transmission during tissue morphogenesis.
8,347 downloads developmental biology
One of the earliest and most significant events in embryonic development is zygotic genome activation (ZGA). In several species, bulk transcription begins at the mid-blastula transition (MBT) when, after a certain number of cleavages, the embryo attains a particular nuclear-to-cytoplasmic (N/C) ratio, maternal repressors become sufficiently diluted, and the cell cycle slows down. Here we resolve the frog ZGA in time and space by profiling RNA polymerase II (RNAPII) engagement and its transcriptional readout. We detect a gradual increase in both the quantity and the length of RNAPII elongation before the MBT, revealing that >1,000 zygotic genes disregard the N/C timer for their activation, and that the sizes of newly transcribed genes are not necessarily constrained by cell cycle duration. We also find that Wnt, Nodal and BMP signaling together generate most of the spatio-temporal dynamics of regional ZGA, directing the formation of orthogonal body axes and proportionate germ layers.
8,176 downloads developmental biology
Size trade-offs of visual versus olfactory organs is a pervasive feature of animal evolution. Comparing Drosophila species, we find that larger eyes correlate with smaller antennae, where olfactory organs reside, and narrower faces. We demonstrate that this trade-off arises through differential subdivision of the head primordium into visual versus non-visual fields. Specification of the visual field requires a highly-conserved eye development gene called eyeless in flies and Pax6 in humans. We discover that changes in the temporal regulation of eyeless expression during development is a conserved mechanism for sensory trade-offs within and between Drosophila species. We identify a natural single nucleotide polymorphism in the cis-regulatory region of eyeless that is sufficient to alter its temporal regulation and eye size. Because Pax6 is a conserved regulator of sensory placode subdivision, we propose that alterations in the mutual repression between sensory territories is a conserved mechanism for sensory trade-offs in animals.
8,066 downloads developmental biology
Small RhoGTPases and Myosin-II direct cell shape changes and movements during tissue morphogenesis. Their activities are tightly regulated in space and time to specify the desired pattern of contractility that supports tissue morphogenesis. This is expected to stem from polarized surface stimuli and from polarized signaling processing inside cells. We examined this general problem in the context of cell intercalation that drives extension of the Drosophila ectoderm. In the ectoderm, G protein coupled receptors (GPCRs) and their downstream heterotrimeric G proteins (Gα and Gβγ) activate Rho1 both medial-apically, where it exhibits pulsed dynamics, and at junctions, where its activity is planar polarized (Kerridge et al., 2016; Munjal et al., 2015). However, the mechanisms responsible for polarizing Rho1 activity are unclear. In particular, it is unknown how Rho1 activity is controlled at junctions. We report a division of labor in the mechanisms of Rho1 activation in that distinct guanine exchange factors (GEFs), that serve as activators of Rho1, operate in these distinct cellular compartments. RhoGEF2 acts uniquely to activate medial-apical Rho1. Although RhoGEF2 is recruited both medial-apically and at junctions by Gα12/13-GTP, also called Concertina (Cta) in Drosophila, its activity is restricted to the medial-apical compartment. Furthermore, we characterize a novel RhoGEF, p114RhoGEF/Wireless (Wrl), and report its requirement for cell intercalation in the extending ectoderm. p114RhoGEF/Wireless activates Rho1 specifically at junctions. Strikingly it is restricted to adherens junctions and is under Gβ13F/Gγ1 control. Gβ13F/Gγ1 activates junctional Rho1 and exerts quantitative control over planar polarization of Rho1. In particular, overexpression of Gβ13F/Gγ1 leads to hyper planar polarization of Rho1 and MyoII. Finally, we found that p114RhoGEF/Wireless is absent in the mesoderm, arguing for a tissue-specific control over junctional Rho1 activity. These results shed light on the mechanisms of polarization of Rho1 activity in different cellular compartments and reveal that distinct GEFs are sensitive tuning parameters of cell contractility in remodeling epithelia.
6,372 downloads developmental biology
The observation of individuals attaining remarkable ages, and their concentration into geographic sub-regions or blue zones, has generated considerable scientific interest. Proposed drivers of remarkable longevity include high vegetable intake, strong social connections, and genetic markers. Here, we reveal new predictors of remarkable longevity and supercentenarian status. In the United States supercentenarian status is predicted by the absence of vital registration. In the UK, Italy, Japan, and France remarkable longevity is instead predicted by regional poverty, old-age poverty, material deprivation, low incomes, high crime rates, a remote region of birth, worse health, and fewer 90+ year old people. In addition, supercentenarian birthdates are concentrated on the first of the month and days divisible by five: patterns indicative of widespread fraud and error. As such, relative poverty and missing vital documents constitute unexpected predictors of centenarian and supercentenarian status, and support a primary role of fraud and error in generating remarkable human age records. ### Competing Interest Statement The authors have declared no competing interest.
5,836 downloads developmental biology
Ricard Argelaguet, Hisham Mohammed, Stephen J Clark, L Carine Stapel, Christel Krueger, Chantriolnt-Andreas Kapourani, Yunlong Xiang, Courtney Hanna, Sebastien Smallwood, Ximena Ibarra-Soria, Florian Buettner, Guido Sanguinetti, Felix Krueger, Wei Xie, Peter Rugg-Gunn, Gavin Kelsey, Wendy Dean, Jennifer Nichols, Oliver Stegle, John C Marioni, Wolf Reik
Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan. Recent studies employing single cell RNA-sequencing have identified major transcriptional changes associated with germ layer specification. Global epigenetic reprogramming accompanies these changes, but the role of the epigenome in regulating early cell fate choice remains unresolved, and the coordination between different epigenetic layers is unclear. Here we describe the first single cell triple-omics map of chromatin accessibility, DNA methylation and RNA expression during the exit from pluripotency and the onset of gastrulation in mouse embryos. We find dynamic dependencies between the different molecular layers, with evidence for distinct modes of epigenetic regulation. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of local lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements, driven by loss of methylation in enhancer marks and a concomitant increase of chromatin accessibility. In striking contrast, the epigenetic landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or epigenetically remodelled prior to overt cell fate decisions during gastrulation, providing the molecular logic for a hierarchical emergence of the primary germ layers.
4,940 downloads developmental biology
In situ hybridization based on the mechanism of hybridization chain reaction (HCR) has addressed multi-decade challenges to imaging mRNA expression in diverse organisms, offering a unique combination of multiplexing, quantitation, sensitivity, resolution, and versatility. Here, with third-generation in situ HCR, we augment these capabilities using probes and amplifiers that combine to provide automatic background suppression throughout the protocol, ensuring that even if reagents bind non-specifically within the sample they will not generate amplified background. Automatic background suppression dramatically enhances performance and robustness, combining the benefits of higher signal-to-background with the convenience of using unoptimized probe sets for new targets and organisms. In situ HCR v3.0 enables multiplexed quantitative mRNA imaging with subcellular resolution in the anatomical context of whole-mount vertebrate embryos, multiplexed quantitative mRNA flow cytometry for high-throughput single-cell expression profiling, and multiplexed quantitative single-molecule mRNA imaging in thick autofluorescent samples.
4,648 downloads developmental biology
The molecular mechanisms and signalling pathways that regulate the in vitro preservation of distinct pluripotent stem cell configurations, and their induction in somatic cells via direct reprogramming approaches, continue to constitute a highly exciting area of research. In this review, we provide an integrative synthesis on recent discoveries related to isolating unique naive and primed pluripotent stem cell states with altered functional and molecular characteristics, and from different species. We overview pathways underlying pluripotent state transitions and interconversion in vitro and in vivo. We conclude by highlighting unresolved key questions, future directions and potential novel applications of such dynamic pluripotent cell states.
4,535 downloads developmental biology
The bone marrow (BM) constitutes the primary site for life-long blood production and skeletal regeneration. However, its cellular composition and the spatial organization into distinct niches remains controversial. Here, we combine single-cell and spatially resolved transcriptomics to systematically map the molecular and cellular composition of the endosteal, sinusoidal, and arteriolar BM niches. This allowed us to transcriptionally profile all major BM resident cell types, determine their localization, and clarify the cellular and spatial sources of key growth factors and cytokines. Our data demonstrate that previously unrecognized Cxcl12-abundant reticular (CAR) cell subsets (i.e. Adipo- and Osteo- CAR cells) differentially localize to sinusoidal or arteriolar surfaces, locally act as professional cytokine secreting cells, and thereby establish distinct peri-vascular micro-niches. Importantly, we also demonstrate that the 3-dimensional organization of the BM can be accurately inferred from single-cell gene expression data using the newly developed RNA-Magnet algorithm. Together, our study reveals the cellular and spatial organization of BM niches, and offers a novel strategy to dissect the complex organization of whole organs in a systematic manner.
4,410 downloads developmental biology
Understanding the emergence of complex multicellular organisms from single totipotent cells, or ontogenesis, represents a foundational question in biology. The study of mammalian development is particularly challenging due to the difficulty of monitoring embryos in utero, the variability of progenitor field sizes, and the indeterminate relationship between the generation of uncommitted progenitors and their progression to subsequent stages. Here, we present a flexible, high information, multi-channel molecular recorder with a single cell (sc) readout and apply it as an evolving lineage tracer to define a mouse cell fate map from fertilization through gastrulation. By combining lineage information with scRNA-seq profiles, we recapitulate canonical developmental relationships between different tissue types and reveal an unexpected transcriptional convergence of endodermal cells from extra-embryonic and embryonic origins, illustrating how lineage information complements scRNA-seq to define cell types. Finally, we apply our cell fate map to estimate the number of embryonic progenitor cells and the degree of asymmetric partitioning within the pluripotent epiblast during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems to facilitate a quantitative framework for describing developmental processes.
4,375 downloads developmental biology
Multicellular systems develop from single cells through a lineage, but current lineage tracing approaches scale poorly to whole organisms. Here we use genome editing to progressively introduce and accumulate diverse mutations in a DNA barcode over multiple rounds of cell division. The barcode, an array of CRISPR/Cas9 target sites, records lineage relationships in the patterns of mutations shared between cells. In cell culture and zebrafish, we show that rates and patterns of editing are tunable, and that thousands of lineage-informative barcode alleles can be generated. By sampling hundreds of thousands of cells from individual zebrafish, we find that most cells in adult zebrafish organs derive from relatively few embryonic progenitors. Genome editing of synthetic target arrays for lineage tracing (GESTALT) will help generate large-scale maps of cell lineage in multicellular systems.
4,295 downloads developmental biology
Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide and can occur because of aging, hormonal dysfunction, autoimmunity, or as a side effect of cancer treatment (Gilhar et al., 2012; Petukhova et al., 2010). Methods that can be used to regrow hair are highly sought after, but lacking. Here we report that hair regeneration can be stimulated by small molecules that activate autophagy, including the longevity metabolites α-ketoglutarate and α-ketobutyrate, and the prescription drugs rapamycin and metformin which impinge on TOR and AMPK signaling.
4,229 downloads developmental biology
Hundreds of cell types are generated during development, but their lineage relationships are largely elusive. Here we report a technology, scGESTALT, which combines cell type identification by single-cell RNA sequencing with lineage recording by cumulative barcode editing. We sequenced ~60,000 transcriptomes from the juvenile zebrafish brain and identified more than 100 cell types and marker genes. We engineered an inducible system that combines early and late barcode editing and isolated thousands of single-cell transcriptomes and their associated barcodes. The large diversity of edited barcodes and cell types enabled the generation of lineage trees with hundreds of branches. Inspection of lineage trajectories identified restrictions at the level of cell types and brain regions and helped uncover gene expression cascades during differentiation. These results establish scGESTALT as a new and widely applicable tool to simultaneously characterize the molecular identities and lineage histories of thousands of cells during development and disease.
3,976 downloads developmental biology
Ryan S Ziffra, Chang N Kim, Amy Wilfert, Tychele N. Turner, Maximilian Haeussler, Alex M Casella, Pawel F Przytycki, Anat Kreimer, Katherine S. Pollard, Seth A Ament, Evan E. Eichler, Nadav Ahituv, Tomasz J. Nowakowski
Dynamic changes in chromatin accessibility coincide with important aspects of neuronal differentiation, such as fate specification and arealization and confer cell type-specific associations to neurodevelopmental disorders. However, studies of the epigenomic landscape of the developing human brain have yet to be performed at single-cell resolution. Here, we profiled chromatin accessibility of >75,000 cells from eight distinct areas of developing human forebrain using single cell ATAC-seq (scATACseq). We identified thousands of loci that undergo extensive cell type-specific changes in accessibility during corticogenesis. Chromatin state profiling also reveals novel distinctions between neural progenitor cells from different cortical areas not seen in transcriptomic profiles and suggests a role for retinoic acid signaling in cortical arealization. Comparison of the cell type-specific chromatin landscape of cerebral organoids to primary developing cortex found that organoids establish broad cell type-specific enhancer accessibility patterns similar to the developing cortex, but lack many putative regulatory elements identified in homologous primary cell types. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.
3,971 downloads developmental biology
Development, homeostasis and regeneration of tissues result from the interaction of genetics and mechanics. Kinematics and rheology are two main classes of measurements respectively providing deformations and mechanical properties of a material. They are now applied to living tissues and have contributed to the better understanding of their mechanics. Due to the complexity of living tissues, however, a third class of mechanical measurements, that of in situ forces and stresses, appears to be increasingly important to elaborate realistic models of tissue mechanics. We review here several emerging techniques of this class, their fields of applications, their advantages and limitations, and their validations. We argue that they will strongly impact on our understanding of developmental biology in the near future.
3,959 downloads developmental biology
We analyzed all published reports of individuals not exposed to syntactic language until puberty: two feral children, who grew up without hearing any language, and eight deaf linguistic isolates, who grew up communicating to their families using homesign or kitchensign, a system of gestures which allows them to communicate simple commands but lacks much in the way of syntax. A common observation in these individuals is the lifelong difficulty understanding syntax and spatial prepositions, even after many years of rehabilitation. This debilitating condition stands in stark contrast to linguistic isolates' performance on memory as well as semantic tests: they could easily remember hundreds of newly learned words and identify previously seen objects by name. The lack of syntactic language comprehension in linguistic isolates may stem from inability to understand words and/or grammar or inability to mentally synthesize known objects into novel configurations. We have previously shown that purposeful construction of novel mental images is the function of the lateral prefrontal cortex (LPFC) ability to dynamically control posterior cortex neurons . Here we have ranked all tests performed on linguistic isolates by their reliance on the LPFC control of the posterior cortex: a) the amount of posterior cortex territory that needs to be recruited by the LPFC and b) the number of disparate objects that have to be combined together by the LPFC in order to answer the test question. According to our analysis, linguistic isolates performed well in all tests that did not involve the LPFC control of the posterior cortex, showed decreasing scores in tests that involved greater recruitment of the posterior cortex by the LPFC, and failed in tests that involved greatest recruitment of posterior cortex necessary for mental synthesis of multiple objects. This pattern is consistent with inadequate frontoposterior connections in linguistic isolates. We discuss implications of these findings for the importance of early syntactic language exposure in formation of frontoposterior connections.
3,605 downloads developmental biology
Brian S. Clark, Genevieve L. Stein-O’Brien, Fion Shiau, Gabrielle H. Cannon, Emily Davis, Thomas Sherman, Fatemeh Rajaii, Rebecca E. James-Esposito, Richard M. Gronostajski, Elana J. Fertig, Loyal A. Goff, Seth Blackshaw
Precise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the extensive cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single cell RNA-sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each of the major retinal cell types. These data identify transitions in gene expression between early and late-stage retinal progenitors, as well as a classification of neurogenic progenitors. We identify here the NFI family of transcription factors (Nfia, Nfib, and Nfix) as genes with enriched expression within late RPCs, and show they are regulators of bipolar interneuron and Muller glia specification and the control of proliferative quiescence.
3,563 downloads developmental biology
Roser Vento-Tormo, Mirjana Efremova, Rachel A. Botting, Margherita Y. Turco, Miquel Vento-Tormo, Kerstin B Meyer, Jongeun Park, Emily Stephenson, K Polanski, Rebecca P. Payne, Angela Goncalves, Angela Zou, Johan Henriksson, Laura Wood, Steve Lisgo, Andrew Filby, Gavin J Wright, Michael J. T. Stubbington, Muzlifah Haniffa, Ashley Moffett, Sarah A. Teichmann
During the early weeks of human pregnancy, the fetal placenta implants into the uterine mucosa (decidua) where placental trophoblast cells intermingle and communicate with maternal cells. Here, we profile transcriptomes of ~50,000 single cells from this unique microenvironment, sampling matched first trimester maternal blood and decidua, and fetal cells from the placenta itself. We define the cellular composition of human decidua, revealing five distinct subsets of decidual fibroblasts with differing growth factors and hormone production profiles, and show that fibroblast states define two distinct decidual layers. Among decidual NK cells, we resolve three subsets, each with a different immunomodulatory and chemokine profile. We develop a repository of ligand-receptor pairs (www.CellPhoneDB.org) and a statistical tool to predict the probability of cell-cell interactions via these pairs, highlighting specific interactions between decidual NK cells and invading fetal extravillous trophoblast cells, maternal immune and stromal cells. Our single cell atlas of the maternal-fetal interface reveals the cellular organization and interactions critical for placentation and reproductive success.
3,557 downloads developmental biology
Formation and segregation of cell lineages building the vertebrate heart have been studied extensively by genetic cell tracing techniques and by analysis of single marker gene expression but the underlying gene regulatory networks driving cell fate transitions during early cardiogenesis are only partially understood. Here, we comprehensively characterized mouse cardiac progenitor cells (CPC) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing. By leveraging on cell-to-cell heterogeneity, we identified different previously unknown cardiac sub-populations. Reconstruction of the developmental trajectory revealed that Isl1+ CPC represent a transitional cell population maintaining a prolonged multipotent state, whereas extended expression of Nkx2-5 commits CPC to a unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states, which critically depend on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution.
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