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Results for “Developmental Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 343 records · Page 19Linked to original sources

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗

bioRxiv2017

mTORC1-mediated inhibition of 4EBP1 is essential for Hedgehog (HH) signaling and can be targeted to suppress HH-driven medulloblastoma

Mechanistic target of rapamycin (MTOR) cooperates with Hedgehog (HH) signaling, but the underlying mechanisms are incompletely understood. Here, we provide genetic, biochemical, and pharmacologic evidence that MTOR complex 1 (mTORC1)-dependent translation is a prerequisite for HH signaling. The genetic loss of mTORC1 function inhibited HH signaling- driven growth of the cerebellum and medulloblastoma. Inhibiting translation or mTORC1 blocked HH signaling. Depleting 4EBP1, an mTORC1 target that inhibits translation, alleviated the dependence of HH signaling on mTORC1. Consistent with this, phosphorylated 4EBP1 levels were elevated in HH signaling-driven medulloblastomas in mice and humans. In mice, an mTORC1 inhibitor suppressed medulloblastoma driven by a mutant SMO that is resistant to an SMO inhibitor in the clinic, prolonging the survival of the mice. Our study reveals mTORC1-mediated translation to be a key component of HH signaling and an important target for treating medulloblastoma and other cancers driven by HH signaling.

developmental biology↗

bioRxiv2017

apterous A Specifies Dorsal Wing Patterns And Sexual Traits In Butterflies

Butterflies have evolved different color patterns on their dorsal and ventral wing surfaces to serve different signaling functions, yet the developmental mechanisms controlling surface-specific patterning are still unknown. Here, we mutate both copies of the transcription factor apterous in Bicyclus anynana butterflies using CRISPR/Cas9 and show that apterous A functions both as a repressor and modifier of ventral wing color patterns, as well as a promoter of dorsal sexual ornaments in males. We propose that the surface-specific diversification of wing patterns in butterflies proceeded via the co-option of apterous A into various gene regulatory networks involved in the differentiation of discrete wing traits. Further, interactions between apterous and sex-specific factors such as doublesex may have contributed to the origin of sexually dimorphic surface-specific patterns. Finally, we discuss the evolution of eyespot pattern diversity in the family Nymphalidae within the context of developmental constraints due to apterous regulation.\n\nSignificance statementButterflies have evolved different wing patterns on their dorsal and ventral wing surfaces that serve different signaling functions. We identify the transcription factor, apterous A, as a key regulator of this surface-specific differentiation in butterflies. We also show a role for apterous A in restricting the developmental origin of a novel trait, eyespots, to just the ventral wing surface. Dorsal-ventral differentiation of tissues is not just restricted to butterfly wings but occurs in many other organs and organisms from arthropods to humans. Thus, we believe that our work will be of interest to a diverse group of biologists and layman alike interested in the role of development in shaping biodiversity.

developmental biology↗

bioRxiv2017

Germ cell connectivity enhances cell death in response to DNA damage in Drosophila testis

Two broadly known characteristics of germ cells in many organisms are their development as a cyst of interconnected cells and their high sensitivity to DNA damage. Here we provide evidence that these characteristics are linked, and that interconnectivity is a mechanism that confers to the Drosophila testis a high sensitivity to DNA damage. We show that all germ cells within a cyst die simultaneously even when only a subset of them exhibit detectable DNA damage. Compromising connectivity results in cysts in which only a subset of germ cells die upon DNA damage, lowering overall germ cell death. Our data indicate that a death-promoting signal is shared through the intercellular connections of germ cells. Taken together, we propose that intercellular connectivity is a mechanism that uniquely increases the sensitivity of the germline to DNA damage, thereby protecting the integrity of gamete genomes that are passed on to the next generation.

developmental biology↗

bioRxiv2017

TGF(beta) Mediated Structural Remodeling Facilitates Optic Fissure Fusion And The Necessity Of BMP Antagonism In This Process

The optic fissure is a transient gap in the developing vertebrate eye, which must be closed as development proceeds. A persisting optic fissure, coloboma, is a major cause for blindness in children. Multiple factors are genetically linked to coloboma formation. However, especially the process of optic fissure fusion is still largely elusive on a cellular and molecular basis.\n\nWe found a coloboma phenotype in mice with a targeted inactivation of the transforming growth factor 2 (TGF{beta}2). Here the optic fissure margins got in touch, however, failed to fuse. Transcriptomic analyses indicated TGF{beta} mediated ECM remodeling during optic fissure fusion. For functional analyses, we switched model systems and made use of zebrafish. We found TGF{beta} ligands expressed in the developing zebrafish eye, and the ligand binding receptor in the optic fissure. Using a new in vivo TGF{beta} signaling reporter, we also found active TGF{beta} signaling in the margins of the optic fissure. We addressed the function of Cadherin 6 (cdh6), one of the TGF{beta} regulated genes, by knock down experiments in zebrafish and found a prominent coloboma phenotype. Cdh6 was often found involved in processes of epithelial to mesenchymal transition (EMT), strengthening our hypothesis that an EMT-like process is also necessary for optic fissure fusion. Furthermore, we found Gremlin 2b (grem2b) and Follistatin a (fsta), homologs of TGF{beta} regulated bone morphogenetic protein (BMP) antagonists, expressed in the optic fissure margins, indicating the necessity of a localized inhibition of BMP signaling. Finally, we show that induced BMP expression is sufficient to inhibit optic fissure fusion. Together with our previous findings this indicates a dual role of BMP signaling during optic fissure closure.\n\nSummary statementTGF{beta} is crucial for optic fissure fusion, involving cdh6. TGF{beta} mediated optic fissure fusion is potentially hampered by BMP signaling, which is blocked by TGF{beta} induced BMP antagonists within the optic fissure margins.

developmental biology↗

bioRxiv2017

C. elegans Flavin Monooxygenases Regulate C. elegans Axon Guidance and Growth Cone Protrusion with UNC-6/Netrin signaling and Rac GTPases

The guidance cue UNC-6/Netrin regulates both attractive and repulsive axon guidance. Our previous work showed that in C. elegans, the attractive UNC-6/Netrin receptor UNC-40/DCC stimulates growth cone protrusion, and that the repulsive receptor, an UNC-5/UNC-40 heterodimer, inhibits growth cone protrusion. We have also shown that inhibition of growth cone protrusion downstream of the UNC-5/UNC-40 repulsive receptor involves Rac GTPases, the Rac GTP exchange factor UNC-73/Trio, and the cytoskeletal regulator UNC-33/CRMP, which mediates Semaphorin-induced growth cone collapse in other systems. The multidomain flavoprotein monooxygenase (FMO) MICAL also mediates growth cone collapse in response to Semaphorin by directly oxidizing F-actin, resulting in depolymerization. The C. elegans genome does not encode a multidomain MICAL-like molecule, but does encode five flavin monooxygenases (FMO-1, -2, -3, -4, and 5) and another molecule, EHBP-1, similar to the non-FMO portion of MICAL.\n\nHere we show that FMO-1, FMO-4, FMO-5, and EHBP-1 may play a role in UNC-6/Netrin directed repulsive guidance mediated through UNC-40 and UNC-5 receptors. Mutations in fmo-1, fmo-4, fmo-5, and ehbp-1 showed VD/DD axon guidance and branching defects, and variably enhanced unc-40 and unc-5 VD/DD guidance defects. Developing growth cones in vivo of fmo-1, fmo-4, fmo-5, and ehbp-1 mutants displayed excessive filopodial protrusion, and transgenic expression of FMO-5 inhibited growth cone protrusion. Mutations suppressed growth cone inhibition caused by activated UNC-40 and UNC-5 signaling, and activated Rac GTPase CED-10 and MIG-2, suggesting that these molecules are required downstream of UNC-6/Netrin receptors and Rac GTPases. From these studies, we conclude that FMO-1, FMO-4, FMO-5, and EHBP-1 represent new players downstream of UNC-6/Netrin receptors and Rac GTPases that inhibit growth cone filopodial protrusion in repulsive axon guidance.\n\nAuthor SummaryMolecular mechanisms of axon repulsion mediated by UNC-6/Netrin are not well understood. Inhibition of growth cone lamellipodial and filopodial protrusion is critical to repulsive axon guidance. Previous work identified a novel pathway involving Rac GTPases and the cytoskeletal interacting molecule UNC-33/CRMP required for UNC-6/Netrin-mediated inhibition of growth cone protrusion. In other systems, CRMP mediates growth cone collapse in response to semaphorin. Here we demonstrate a novel role of flavoprotein monooxygenases (FMOs) in repulsive axon guidance and inhibition of growth cone protrusion downstream of UNC-6/Netrin signaling and Rac GTPases. In Drosophila and vertebrates, the multidomain MICAL FMO mediates semaphorin-dependent growth cone collapse by direct oxidation and depolymerization of F-actin. The C. elegans genome does not encode a multidomain MICAL-like molecule, and we speculate that the C. elegans FMOs might have an equivalent role downstream of UNC-6/Netrin signaling. Indeed, we show that EHBP-1, similar to the non-FMO portion of MICAL, also controls repulsive axon guidance and growth cone inhibition, suggesting that in C. elegans, the functions of the multidomain MICAL molecule might be distributed across different molecules. In sum, we show conservation of function of molecules involved in semaphorin growth cone collapse with inhibition of growth cone protrusion downstream of UNC-6/Netrin signaling.

developmental biology↗

bioRxiv2017

PHRED-1 Is A Divergent Neurexin-1 Homolog That Organizes Muscle Fibers And Patterns Organs During Regeneration

Regeneration of body parts requires the replacement of multiple cell types. To dissect this complex process, we utilized planarian flatworms that are capable of regenerating any tissue after amputation. An RNAi screen for genes involved in regeneration of the pharynx identified a novel gene, Pharynx regeneration defective-1 (PHRED-1) as essential for normal pharynx regeneration. PHRED-1 is a predicted transmembrane protein containing EGF, Laminin G, and WD40 domains, is expressed in muscle, and has predicted homologs restricted to other lophotrochozoan species. Knockdown of PHRED-1 causes abnormal regeneration of muscle fibers in both the pharynx and body wall muscle. In addition to defects in muscle regeneration, knockdown of PHRED-1 or the bHLH transcription factor MyoD also causes defects in muscle and intestinal regeneration. Together, our data demonstrate that muscle plays a key role in restoring the structural integrity of closely associated organs, and in planarians it may form a scaffold that facilitates normal intestinal branching.\n\nGraphical Abstract\n\nHighlights-PHRED-1 is a predicted transmembrane protein that contains Laminin G, EGF and WD40 domains\n\n-PHRED-1 is required for normal muscle patterning during regeneration\n\n-phred-1 is expressed in muscle cells\n\n-Muscle forms an essential scaffold for regeneration

developmental biology↗

bioRxiv2017

Cells From The Same Lineage Switch From Reduction To Enhancement Of Size Variability In Arabidopsis Sepals

Organs form with remarkably consistent sizes and shapes during development, whereas a high variability in size and growth is observed at cell level. Given this contrast, it is unclear how such consistency at organ scale can emerge from cellular behavior. We examine the growth of cell lineages, or groups of cells that are the progeny of a single mother cell. At early stages of the lineage, we find that initially smaller lineages grow faster than the larger ones reducing variability in lineage size, a phenomenon we refer to as size uniformization. In contrast at later stages of the lineage, size variability is enhanced when initially larger cell lineages grow faster than the smaller ones. Our results imply that the cell lineage changes its growth pattern at a tipping point. Finally, we found that the growth heterogeneity of individual cells within a lineage is correlated with fast growth of the lineage. Consequently, fast growing lineages show greater cell growth heterogeneity, leading to uniformization in lineage size. Thus, cellular variability in growth contributes toward decreasing variability of cell lineages throughout the sepal.

developmental biology↗

bioRxiv2017

Dense Bicoid Hubs Accentuate Binding along the Morphogen Gradient

Morphogen gradients direct the spatial patterning of developing embryos, however, the mechanisms by which these gradients are interpreted remain elusive. Here we perform in vivo single molecule imaging in early Drosophila melanogaster embryos of the transcription factor Bicoid that forms a gradient and initiates patterning along the anteroposterior axis. We observe that Bicoid binds to DNA with a rapid off-rate, such that its average occupancy at target loci is on-rate dependent, a property required for concentration-sensitive regulation. Surprisingly, we also observe abundant specific DNA binding in posterior nuclei, where Bicoid levels are vanishingly low. Live embryo imaging reveals spatiotemporal \"hubs\" of local high Bicoid concentration that are dependent on the ubiquitous maternal factor Zelda. We propose that localized modulation of transcription factor on-rates via clustering, provides a general mechanism to facilitate binding to low-affinity targets, and that this may be a prevalent feature directing other developmental transcription networks.

developmental biology↗

bioRxiv2017

Concentration Dependent Chromatin States Induced by the Bicoid Morphogen Gradient

In Drosophila, graded expression of the maternal transcription factor Bicoid (Bcd) provides positional information to activate target genes at different positions along the anterior-posterior axis. We have measured the genome-wide binding profile of Bcd using ChIP-seq in embryos expressing single, uniform levels of Bcd protein, and grouped Bcd-bound targets into four classes based on occupancy at different concentrations. By measuring the biochemical affinity of target enhancers in these classes in vitro and genome-wide chromatin accessibility by ATAC-seq, we found that the occupancy of target sequences by Bcd is not primarily determined by Bcd binding sites, but by chromatin context. Bcd drives an open chromatin state at a subset its targets. Our data support a model where Bcd influences chromatin structure to gain access to concentration-sensitive targets at high concentrations, while concentration-insensitive targets are found in more accessible chromatin and are bound at low concentrations.

developmental biology↗

bioRxiv2017

Vimentin Plays A Functional Role In Mammary Gland Regeneration

In the mammary gland, vimentin intermediate filaments are expressed in stromal cells and in basal epithelial cell populations including gland-reconstituting mammary stem cells (MaSC), with largely undefined functions. Here, we studied how vimentin deficiency affects mouse mammary gland development. Our results demonstrate that in adult vimentin knockout mice (Vim-/-) mammary ductal outgrowth is delayed. The adult Vim-/- glands are characterised by dilated ducts, an imbalance in the proportion of basal to luminal mammary epithelial cells and a reduction in cells expressing Slug (Snai2), an established MaSC regulator. All of these features are indicative of reduced progenitor cell activity. Accordingly, isolated Vim-/- mammary epithelial cells display reduced capacity to form mammospheres, and altered organoid structure, compared to wt counterparts, when plated in a 3D matrix in vitro. Importantly, altered basal epithelial cell number translates into defects in Vim-/- mammary gland regeneration in vivo in cleared fat pad transplantation studies. Furthermore, we show that vimentin contributes to stem-like cell properties in triple negative MDA-MB-231 breast cancer cells, wherein vimentin depletion reduces tumorsphere formation and alters expression of breast cancer stem cell-associated surface markers. Together, our findings identify vimentin as a positive regulator of stemness in the developing mouse mammary gland and in breast cancer cells.

developmental biology↗

bioRxiv2017

The Effect Of Nipped-B-Like (Nipbl) Haploinsufficiency On Genome-Wide Cohesin Binding And Target Gene Expression: Modeling Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis, but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, the presence of multiple gene expression changes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl +/- mice that recapitulate the CdLS phenotype. We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Thus, decreased cohesin binding at the gene regions directly contributes to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.

developmental biology↗

bioRxiv2017

Sex Differentiation In Grayling (Salmonidae) Goes Through An All-Male Stage And Is Delayed In Genetic Males Who Instead Grow Faster

Fish can be threatened by distorted sex ratios that arise during sex differentiation. It is therefore important to understand sex determination and differentiation, especially in river-dwelling fish that are often exposed to environmental factors that may interfere with sex differentiation. However, sex differentiation is not sufficiently understood in keystone taxa such as the Thymallinae, one of the three salmonid subfamilies. Here we study a wild grayling (Thymallus thymallus) population that suffers from distorted sex ratios. We found sex determination in the wild and in captivity to be genetic and linked to the sdY locus. We therefore studied sex-specific gene expression in embryos and early larvae that were bred and raised under different experimental conditions, and we studied gonadal morphology in five monthly samples taken after hatching. Significant sex-specific changes in gene expression (affecting about 25,000 genes) started around hatching. Gonads were still undifferentiated three weeks after hatching, but about half of the fish showed immature testes around seven weeks after hatching. Over the next few months, this phenotype was mostly replaced by the \"testis-to-ovary\" or \"ovaries\" phenotypes. The gonads of the remaining fish, i.e. approximately half of the fish in each sampling period, remained undifferentiated until six months after fertilization. Genetic sexing of the last two samples revealed that fish with undifferentiated gonads were all males, who, by that time, were on average larger than the genetic females (verified in 8-months old juveniles raised in another experiment). Only 12% of the genetic males showed testicular tissue six months after fertilization. We conclude that sex differentiation starts around hatching, goes through an all-male stage for both sexes (which represents a rare case of \"undifferentiated\" gonochoristic species that usually go through an all-female stage), and is delayed in males who, instead of developing their gonads, grow faster than females during these juvenile stages.\n\nAuthor contributionMRR and CW initiated the project. DM, OS, AU, LMC, LW, and CW sampled the adult fish, did the experimental in vitro fertilizations, and prepared the embryos for experimental rearing in the laboratory. All further manipulations on the embryos and the larvae were done by DM, OS, AU, LMC, and LW. The RNA-seq data were analyzed by OS, JR, and MRR, the histological analyses were done by DM, supervised by SK, and the molecular genetic sexing was performed by DM, OS, AU, and KBM. DM, OS, and CW performed the remaining statistical analyses and wrote the first version of the manuscript that was then critically revised by all other authors.

developmental biology↗

bioRxiv2017

Towards An Understanding Of Spiral Patterning In The Sargassum muticum Shoot Apex

In plants and parenchymatous brown algae the body arises through the activity of an apical meristem (a niche of cells or a single cell). The meristem produces lateral organs in specific patterns, referred to as phyllotaxis. In plants, two different control mechanisms have been proposed - one is position-dependent and relies on morphogen accumulation at future organ sites whereas the other is a lineage-based system which links phyllotaxis to the apical cell division pattern. Here we examine the apical patterning of the brown alga, Sargassum muticum, which exhibits spiral phyllotaxis (137.5{degrees} angle) and an unlinked apical cell division pattern. The Sargassum apex presents characteristics of a self-organising system, similar to plant meristems. We were unable to correlate the plant morphogen auxin with bud positioning in Sargassum, nor could we predict cell wall softening at new bud sites. Our data suggests that in Sargassum muticum there is no connection between phyllotaxis and the apical cell division pattern indicating a position-dependent patterning mechanism may be in place. The underlying mechanisms behind the phyllotactic patterning appear to be distinct from those seen in plants.\n\nSummaryThe brown alga Sargassum muticum displays spiral phyllotaxis developed from a position-dependent self-organising mechanism, different from that understood in plants.

developmental biology↗

bioRxiv2017

Regulating prospero mRNA Stability Determines When Neural Stem Cells Stop Dividing

During Drosophila and vertebrate brain development, the conserved transcription factor Prospero/Prox1 is an important regulator of the transition between proliferation and differentiation. Prospero level is low in neural stem cells and their immediate progeny, but is upregulated in larval neurons and it is unknown how this process is controlled. Here, we use single molecule fluorescent in situ hybridisation to show that larval neurons selectively transcribe a long prospero mRNA isoform containing a 15 kb 3 untranslated region, which is bound in the brain by the conserved RNA-binding protein Syncrip/hnRNPQ. Syncrip binding increases the mRNA stability of the long prospero isoform, which allows an upregulation of Prospero protein production. Our findings highlight a regulatory strategy involving alternative polyadenylation followed by differential post-transcriptional regulation.

developmental biology↗

bioRxiv2017

Imp/Syp Temporal Gradients Govern Decommissioning Of Drosophila Neural Stem Cells

Timing of Drosophila neuroblast decommissioning is controlled in a lineage-specific manner. Following a prepupal ecdysone pulse, the ecdysone receptor and mediator complex cause neuroblasts to shrink. Shrinking is followed by nuclear accumulation of Prospero and cell cycle exit. Only mushroom body (MB) neuroblasts escape early pupal termination. Here, we demonstrate that the opposing temporal gradients of Imp and Syp RNA-binding proteins that govern temporal fate also regulate neuroblast decommissioning. The Imp gradient declines slower in MB neuroblasts so they still express Imp when it is absent from others. The presence of Imp in MB neuroblasts prevents decommissioning partly through inhibiting the mediator complex. Moreover, a timely induction of Imp can protect many non-MB neuroblasts from aging. We also show that the increasing Syp gradient permits Prospero accumulation and neuroblast termination. Together our results reveal that progeny temporal fate and progenitor decommissioning are co-regulated in protracted neuronal lineages.

developmental biology↗

bioRxiv2017

Deciphering The Developmental Program In The Ascidian Ciona intestinalis Just Prior To Gastrulation

The embryo of the ascidian Ciona intestinalis displays striking anatomical simplicity, with an invariant cleavage pattern during development. It has a monoploid genome like the model organisms Drosophila melanogaster and Caenorhabditis elegans, whereas vertebrates generally exhibit tetraploidy. In this study, I took advantage of these characteristics to investigate the development of the organism as one reverse-engineers an industrial product. First, the spatial expression of 211 genes was digitalized. Some genes showed variable expression patterns, which might reflect multiple snapshots of a single temporally dynamic expression at different times. Several developmental territories of the embryo were considered to be very similar to each other; however, this digitalization of gene expression patterns showed that differences occurred between individual blastomeres even within a single developmental territory. Furthermore, Ciona Brachyury (Ci-Bra) was expressed in those blastomeres in which both Fox (forkhead-box) A-a and Zic (zinc-finger) L were expressed, these proteins being upstream regulators of Ci-Bra. The approach described enables the developmental program to be studied in silico.\n\nSUMMARY STATEMENTA detailed expansion of our knowledge on an animal developmental program by using already published gene expression data with the aid of computers

developmental biology↗

bioRxiv2017

Geometrical confinement guides Brachyury self-patterning in embryonic stem cells.

During embryogenesis, signaling molecules initiate cell diversification, sometimes via stochastic processes, other times via the formation of long range gradients of activity which pattern entire fields of cells. Such mechanisms are not insensitive to noise (Lander, 2011), yet embryogenesis is a remarkably robust process suggesting that multiple layers of regulations secure patterning during development. In the present study, we present a proof of concept according to which an asymmetric pattern of gene expression obtained from a spatially disorganised population of cells can be guided by the geometry of the environment in a reproducible and robust manner. We used ESC as a model system whithin which multiple developmental cell states coexist (MacArthur and Lemischka, 2013; Smith, 2017; Torres-Padilla and Chambers, 2014). We first present evidence that a reciprocal regulation of genes involved in the establishment of antero-posterior polarity during peri-implantation stages of mouse development is spontaneously occuring within ESC. We then show that a population of cells with primitive streak characteristics localise in regions of high curvature and low cell density. Finally, we show that this patterning did not depend on self-organised gradients of morphogen activity but instead could be attributed to positional rearrangements. Our findings unveil a novel role for tissue geometry in guiding the self-patterning of primitive streak cells and provide a framework to further refine our understanding of symmetry breaking events occuring in ESC aggregates. Finally, this work demonstrates that the self-patterning of a specific population of ESC, Brachyury positive cells in this case, can be directed by providing engineered external geometrical cues.

developmental biology↗