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Results for “Developmental Biology”

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bioRxiv2019

A contractile acto-myosin belt promotes growth anisotropy during the early stages of pectoral fin development in zebrafish.

The zebrafish pectoral fin is an in vivo model for vertebrate limb formation, well suited to investigate the integration of molecular and cellular dynamics, the results of which translate into shaping the limb bud. We used the ratio between the lengths of the anterior-posterior (AP) and dorso-ventral (DV) axes as the descriptor of how fin shape changes over time. We showed that fin shape transitions from close to hemi-spherical (ratio 1. 36 {+/-} 0.11) to semi-ellipsoid (ratio 1.64 {+/-} 0.04) between 33 and 46 hours post fertilization (hpf). This shape transition coincided with the formation of a contractile \"actin belt\" at the distal rim of the fin bud along its AP axis. The actin belt emerged from a central position and expanded on both sides along the distal rim of the fin, thus marking the DV boundary between two rows of ectodermal cells. Formation of the actin belt depended on Rac protein activity, as suggested by FRET measurements using a Rac biosensor. 3D+time imaging of the developing fin in Rac-deficient embryos showed that anisotropic growth of the fin depends on the actin belt. Indeed, actin belt formation was dramatically reduced or even absent in the embryos without proper Rac activity. This correlated with isotropic growth of the fin bud from normal shape at 33 hpf to quasi hemispherical shape with AP/DV ratio ~1 13 hours later, without affecting cell number and overall bud volume. We propose that the formation of a contractile acto-myosin belt is essential to drive the pectoral fins early anisotropic growth.

developmental biology↗

bioRxiv2019

Evolutionary loss of foot muscle during development with characteristics of atrophy and no evidence of cell death

Many species that run or leap across sparsely vegetated habitats, including horses and deer, evolved the severe reduction or complete loss of foot muscles as skeletal elements elongated and digits were lost, and yet the developmental mechanisms remain unknown. Here, we report the natural loss of foot muscles in the bipedal jerboa, Jaculus jaculus. Although adults have no muscles in their feet, newborn animals have muscles that rapidly disappear soon after birth. We were surprised to find no evidence of apoptotic or necrotic cell death during stages of peak myofiber loss, countering well-supported assumptions of developmental tissue remodeling. We instead see hallmarks of muscle atrophy, including an ordered disassembly of the sarcomere associated with upregulation of the E3 ubiquitin ligases, MuRF1 and Atrogin-1. We propose that the natural loss of muscle, which remodeled foot anatomy during evolution and development, involves cellular mechanisms that are typically associated with disease or injury.

developmental biology↗

bioRxiv2019

Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development.

The glycosylphosphatidylinositol (GPI) anchor attaches nearly 150 proteins to the cell surface. Patients with pathogenic variants in GPI biosynthetic pathway genes display an array of phenotypes including seizures, developmental delay, dysmorphic facial features and cleft palate. There is virtually no mechanism to explain these phenotypes. we identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypomorphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2). Pgap2 is one of the final proteins in the GPI biosynthesis pathway and is required for anchor maturation. We found the Clpex mutation results in a global decrease in surface GPI expression. Surprisingly, Pgap2 showed tissue specific expression with enrichment in the affected tissues of the Clpex mutant. We found the phenotype in Clpex mutants is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium, as is observed in the GPI anchored Folate Receptor 1-/- mouse. We showed folinic acid supplementation in utero can rescue the cleft lip phenotype in Clpex. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency in the Wnt1-Cre lineage. These mutants developed median cleft lip and palate demonstrating a cell autonomous role for GPI biosynthesis in NCC development.

developmental biology↗

bioRxiv2019

Cyclin A2/Cdk1 is Essential for the in vivo S Phase Entry by Phosphorylating Top2a.

Cyclin-dependent kinase 1 (CDK1) plays essential roles in cell cycle regulation. However, due to the early embryonic lethality of mouse Cdk1 mutants, the in vivo role of CDK1 in regulating cell cycle and embryonic development remains unclear. Here, by generating zebrafish cdk1 mutants using CRISPR/Cas9 system, we show that cdk1-/- embryos exhibit severe microphthalmia accompanied with multiple defects in polarized cell division, S phase entry and M phase progression, cell apoptosis and cell differentiation, but not in interkinetic nuclear migration (IKNM). By informatics analysis, we identified Top2a as a potential downstream target, and Cyclin A2 and Cyclin B1 as partners of Cdk1 in cell cycle. Depletion of either Cyclin A2 or Top2a leads to decreased S phase entry and increased DNA damage response in zebrafish retinal cells, and depletion of Cyclin B1 leads to M phase arrest. Immunoprecipitation shows that Cdk1 and Cyclin A2 physically interact in vivo. Moreover, phosphorylation of Top2a on Serine 1213 (S1213) site is almost absent in either cdk1 or ccna2 mutants, but in not ccnb1 mutants. Furthermore, overexpression of TOP2AS1213, the phosphomimetic form of human TOP2A, rescues S phase entry and microphthalmia defects in cdk1-/- and ccna2-/- embryos. Taken together, our data suggests that Cdk1 interacts with Cyclin A2 to regulate S phase entry through phosphorylating Top2a, and with Cyclin B1 to regulate M phase progression in vivo.

developmental biology↗

bioRxiv2019

WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

The WNT/{beta}-CATENIN pathway is critical for neural crest (NC) formation. However, the effects of the magnitude of the signal remains poorly defined. Here we evaluate the consequences of WNT magnitude variation in a robust model of human NC formation. This model is based on human embryonic stem cells induced by WNT signaling through the small molecule CHIR9902. In addition to its known effect on NC formation, we find that the WNT signal modulates the anterior-posterior axial identity of NCCs in a dose dependent manner, with low WNT leading to anterior OTX+, HOX-NC, and high WNT leading to posterior OTX-, HOX+ NC. Differentiation tests of posterior NC confirm expected derivatives including posterior specific adrenal derivatives, and display partial capacity to generate anterior ectomesenchymal derivatives. Furthermore, unlike anterior NC, posterior NC transit through a TBXT+/SOX2+ neuromesodermal precursor-like intermediate. Finally, we analyze the contributions of other signaling pathways in posterior NC formation, and suggest a critical role for FGF in survival/proliferation, and a requirement of BMP for NC maturation. As expected RA and FGF are able to modulate HOX expression in the posterior NC, but surprisingly, RA supplementation prohibits anterior, but only reduces, posterior NC formation. This work reveals for the first time that the amplitude of WNT signaling can modulate the axial identity of NC cells in humans.

developmental biology↗

bioRxiv2019

A genetic system for generating single-sex progeny in mice

The ability to preselect the sex of livestock is economically beneficial and significantly increases the welfare and proper use of animals. In the poultry industry, for example, almost all males are brutally and unnecessarily killed shortly after hatching. The labor and associated costs of separation of females from males, as well as the massive killing of males, could be reduced by using a system that biases the sex of the progeny. Here, we provide a first proof of concept for such a system by crossing two genetically engineered mouse lines. The maternal line encodes a functional Cas9 protein on an autosomal chromosome, whereas the paternal line encodes guide RNAs on the Y chromosome targeting vital mouse genes. After fertilization, the presence of both the Y-encoded guide RNAs from the paternal sperm and the Cas9 protein from the maternal egg target the vital genes in males. We show that this breeding consequently self-destructs solely the males. Our results pave the way for a biased sex production of livestock, thus saving labor, costs, and eliminating substantial animal suffering.

developmental biology↗

bioRxiv2019

Defining the dynamic chromatin landscape of nephron progenitors

Six2+ cap mesenchyme cells, also called nephrons progenitor cells (NPC), are precursors of all epithelial cell types of the nephron, the filtering unit of the kidney. Current evidence indicates that perinatal \"old\" NPC have a greater tendency to exit the progenitor niche and differentiate into nascent nephrons than their embryonic \"young\" counterpart. Understanding the underpinnings of NPC aging may offer insights to rejuvenate old NPC and expand the progenitor pool. Here, we compared the chromatin landscape of young and old NPC and found common features reflecting their shared lineage but also intrinsic differences in chromatin accessibility and enhancer landscape supporting the view that old NPC are epigenetically poised for differentiation. Annotation of open chromatin regions and active enhancers uncovered the transcription factor Bach2 as a potential link between the pro-renewal MAPK/AP1 and pro-differentiation Six2/b-catenin pathways that might be of critical importance in regulation of NPC fate. Our data provide the first glimpse of the dynamic chromatin landscape of NPC and serve as a platform for future studies of the impact of genetic or environmental perturbations on the epigenome of NPC.\n\nSummary statementHilliard et al. investigated the chromatin landscape of native Six2+ nephron progenitors across their lifespan. They identified age-dependent changes in accessible chromatin and regulatory regions supporting the view that old nephron progenitors are epigenetically poised for differentiation.

developmental biology↗

bioRxiv2019

Anterior Cleft Palate due to Cbfb deficiency and its rescue by folic acid

Core binding factor {beta} (Cbfb) is a cofactor of Runx transcription factors. Among Runx transcription factors, Runx1 is a prerequisite for anterior-specific palatal fusion. However, whether Cbfb serves as a modulator or obligatory factor in Runx signaling that regulates palatogenesis is unclear. We herein report that Cbfb is essential and indispensable in anterior palatogenesis. Palatal fusion in Cbfb mutants is disturbed due to failed disintegration of the fusing epithelium specifically at the anterior portion, as is observed in Runx1 mutants. In this mutants, the Tgfb3 expression is disturbed at the corresponding area of the failed palatal fusion, where phosphorylation of Stat3 is also disturbed. TGFB3 protein rescues the palatal fusion in vitro. Strikingly, the anterior cleft palate in Cbfb mutants is further rescued by pharmaceutical application of folic acid that activates suppressed Stat3 phosphorylation and Tgfb3 expression in vitro. With these findings, we provide the first evidence that Cbfb is a prerequisite for anterior palatogenesis as an obligatory cofactor in the Runx1/Cbfb-Stat3-Tgfb3 signaling axis. Furthermore, the rescue of the mutant cleft palate using folic acid may elucidate potential therapeutic targets by Stat3 modification for the prevention and pharmaceutical intervention of cleft palate.\n\nSummary StatementEpithelial deletion of Cbfb results in an anterior cleft palate with impaired fusion of the palatal process and folic acid application rescues the mutant phenotype with Stat3 activation in vitro.

developmental biology↗

bioRxiv2019

The transcription factor TCF7L2 functions as a terminal selector in thalamic and habenular regions of the brain

Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but few examples of such regulators have been provided in vertebrates. TCF7L2 has been identified as a regulator of efferent outgrowth in the thalamus and habenula. We used a complete and conditional knockout of Tcf7l2 in mice to investigate the hypothesis that TCF7L2 plays a dual role in thalamic neuron differentiation and functions as a terminal selector. Connectivity and cell clustering was disrupted in the thalamo-habenular region in Tcf7l2-/- embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with postnatal Tcf7l2 knockout, the induction of genes that confer terminal electrophysiological features of thalamic neurons was impaired. Many of these genes proved to be TCF7L2 direct targets. The role of TCF7L2 in thalamic terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that maintain regional transcriptional network, control stage-specific genetic programs and induce terminal selection. StatementThe study describes a role of TCF7L2 in neuronal differentiation of thalamic glutamatergic neurons at two developmental stages, highlighting its involvement in the postnatal establishment of critical thalamic electrophysiological features.

developmental biology↗

bioRxiv2019

Epithelial invagination by vertical telescoping

Epithelial bending is a fundamental process that shapes organs during development. All currently known mechanisms involve cells locally changing shape from columnar to wedge-shaped. Often this shape change occurs by cytoskeletal contraction at cell apices (\"apical constriction\") but mechanisms such as basal nuclear positioning (\"basal wedging\") or extrinsic compression are also known. Here we demonstrate a completely different mechanism which occurs without cell wedging. In mammalian salivary glands and teeth, we show that initial invagination occurs through coordinated vertical cell movement. Specifically, we show that cells towards the periphery of the placode move vertically upwards while their more central neighbours move downwards to create the invagination. We further show that this occurs by active cell-on-cell migration: outer cells migrate with an apical leading edge protrusion, depressing the central cells to \"telescope\" the epithelium downwards into the underlaying mesenchyme. Cells remain basally attached to the underlying lamina while their apical protrusions are dynamic and planar polarised centripetally. These protrusions depend on the actin cytoskeleton, and inhibition of the branching molecule Arp2/3 inhibits them and the invagination. FGF and Hedgehog morphogen signals are also required, with FGF providing a directional cue. These findings show that epithelial bending can be achieved by novel morphogenetic mechanism of coordinated cell rearrangement quite distinct from previously recognised invagination processes.

developmental biology↗

bioRxiv2019

Standardised imaging pipeline for phenotyping mouse laterality defects and associated heart malformations, at multiple scales and multiple stages

Laterality defects are developmental disorders resulting from aberrant left/right patterning. In the most severe cases, such as in heterotaxy, they are associated with complex malformations of the heart. Advances in understanding the underlying physiopathological mechanisms have been hindered by the lack of a standardised and exhaustive procedure in mouse models, for phenotyping left/right asymmetries of all visceral organs. Here, we have developed a multimodality imaging pipeline, which combines non-invasive micro-ultrasound imaging, micro-CT and HREM, to acquire 3D images at multiple stages of development and at multiple scales. Based on the position in the uterine horns, we track, in a single individual, the progression of organ asymmetry, the situs of all visceral organs in their thoracic or abdominal environment, together with fine anatomical left/right asymmetries of cardiac segments. We provide reference anatomical images and organ reconstructions in the mouse, and discuss differences with humans. This standardised pipeline, which we validated in a mouse model of heterotaxy, offers a fast and easy-to-implement framework. The extensive 3D phenotyping of organ asymmetry in the mouse uses the clinical nomenclature for direct comparison with patient phenotypes. It is compatible with automated and quantitative image analyses, which is essential to compare mutant phenotypes with incomplete penetrance and gain mechanistic insight into laterality defects.\n\nSummary statementLaterality defects, which combine anomalies in several visceral organs, are challenging to phenotype. We have now developed a standardised approach for multimodality 3D imaging in mice, generating quantifiable phenotypes.

developmental biology↗

bioRxiv2019

A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells

Haematopoietic stem and progenitor cells (HSPCs) maintain the vertebrate blood system throughout life and their emergence from haemogenic endothelium (HE) is regulated by transcription factors such as Gata2. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second zebrafish Gata2 orthologue, gata2b. By 5 days, homozygous gata2a{Delta}i4/{Delta}i4 larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a{Delta}i4/{Delta}i4 adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants are a new paradigm to explore the pathophysiology of GATA2-related deficiencies in vivo.

developmental biology↗

bioRxiv2019

Left Pulmonary Artery in 22q11.2 deletion syndrome. Echocardiographic evaluation in patients without cardiac defects and role of Tbx1 in mice.

Introduction and HypothesisPatients with 22q11 deletion syndrome (22q11.2DS) present, in about 75% of cases, typical patterns of cardiac defects, with a particular involvement on the ventricular outflow tract and great arteries. However, in this genetic condition the dimensions of the pulmonary arteries (PAs) never were specifically evaluated.\n\nWe measured both PAs diameter in patients with 22q11.2DS without cardiac defects, comparing these data to a normal control group. Moreover, we measured the PAs diameter in Tbx1 mutant mice. Finally, a cell fate mapping in Tbx1 mutants was used to study the expression of this gene in the morphogenesis of PAs.\n\nMethodsWe evaluated 58 patients with 22q11.2DS without cardiac defects. The control group consisted of 54 healthy subjects, matched for age and sex. All cases underwent a complete transthoracic echocardiography. Moreover, we crossed Tbx1+/- mice and harvested fetuses. We examined the cardiovascular phenotype of 8 wild type (WT), 37 heterozygous (Tbx1+/-) and 6 null fetuses (Tbx1-/-). Finally, we crossed Tbx1Cre/+mice with R26RmT-mG Cre reporter mice to study Tbx1 expression in the pulmonary arteries.\n\nResultsThe echocardiographic study showed that the mean of the LPA/RPA ratio in 22q11.2DS was smaller (0.80 {+/-} 0.12) than in controls (0.97 {+/-} 0.08; p < 0.0001).\n\nMouse studies resulted in similar data as the size of LPA and RPA was not significantly different in WT embryos, but in Tbx1+/- and Tbx1-/- embryos the LPA was significantly smaller than the RPA in both mutants (P=0.0016 and 0.0043, respectively). We found that Tbx1 is expressed near the origin of the PAs and in their adventitia.\n\nConclusionsChildren with 22q11.2DS without cardiac defects show smaller LPA compared with healthy subjects. Mouse studies suggest that this anomaly is due to haploinsufficiency of Tbx1. These data may be useful in the clinical management of children with 22q11.2DS and should guide further experimental studies as to the mechanisms underlying PAs development.

developmental biology↗

bioRxiv2019

A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

ABSTRACTThe ecdysone pathway was amongst the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone-response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.\n\nSIGNIFICANCENuclear receptors (NRs) are sequence-specific DNA binding proteins that act as intracellular receptors for small molecules such as hormones. Prior work has shown that NRs function as ligand-dependent switches that initiate a cascade of gene expression changes. The extent to which NRs function as direct regulators of downstream genes in these hierarchies remains incompletely understood. Here, we study the role of the NR EcR in metamorphosis of the Drosophila wing. We find that EcR directly regulates many genes at the top of the hierarchy as well as at downstream genes. Further, we find that EcR binds distinct sets of target genes at different developmental times. This work helps inform how hormones elicit tissue- and temporal-specific responses in target tissues.

developmental biology↗

bioRxiv2019

Lactate and glycerol-3-phosphate metabolism cooperatively regulate growth and redox balance during Drosophila melanogaster larval development

The dramatic growth that occurs during Drosophila larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands by increasing carbohydrate metabolism and lactate dehydrogenase (dLDH) activity. The resulting metabolic program is ideally suited to synthesize macromolecules and mimics the manner by which cancer cells rely on aerobic glycolysis. To explore the potential role of Drosophila dLDH in promoting biosynthesis, we examined how dLdh mutations influence larval development. Our studies unexpectantly found that dLdh mutants grow at a normal rate, indicating that dLDH is dispensable for larval biomass production. However, subsequent metabolomic analyses suggested that dLdh mutants compensate for the inability to produce lactate by generating excess glycerol-3-phosphate (G3P), the production of which also influences larval redox balance. Consistent with this possibility, larvae lacking both dLDH and G3P dehydrogenase (GPDH1) exhibit developmental delays, synthetic lethality, and aberrant carbohydrate metabolism. Considering that human cells also generate G3P upon Lactate Dehydrogenase A (LDHA) inhibition, our findings hint at a conserved mechanism in which the coordinate regulation of lactate and G3P synthesis imparts metabolic robustness upon growing animal tissues.

developmental biology↗

bioRxiv2019

Delta/Notch signaling controls neuroepithelial morphogenesis in the zebrafish spinal cord

The morphogenesis of the nervous system requires coordinating the specification and differentiation of neural precursor cells, the establishment of neuroepithelial tissue architecture and the execution of specific cellular movements. How these aspects of neural development are linked is incompletely understood. Here we inactivate a major regulator of embryonic neurogenesis - the Delta/Notch pathway - and analyze the effect on zebrafish central nervous system morphogenesis. While some parts of the nervous system can establish neuroepithelial tissue architecture independently of Notch, Notch signaling is essential for spinal cord morphogenesis. In this tissue, Notch signaling is required to repress neuronal differentiation and promote neuroepithelial apico-basal polarity. Concomitant with a loss of their neuroepithelial properties, Notch signaling deficient cells also alter their morphogenetic behavior. In the wild-type zebrafish neural tube, cells divide at the organ midline to contribute one daughter cell to each organ half. Notch deficient animals fail to display this behavior and therefore form a misproportioned spinal cord. Taken together, our findings show that Notch signaling governs not only the cellular composition but also the morphogenetic shaping of the zebrafish spinal cord.

developmental biology↗

bioRxiv2019

Cell Fate Determining Molecular Switches and Signaling Pathway in Pax7-expressing Somitic Mesoderm

Pax7-expressing progenitor cells in the somitic mesoderm differentiate into multiple lineages, such as brown adipose tissue, dorsal dermis, as well as muscle in the dorsal trunk and the diaphragm; however, the key molecular switches that determine and control the process of lineage commitment and cell fate are unknown. To probe the mechanisms behind mesoderm development, Pax7creER/R26-stop-EYFP embryos were tamoxifen-induced at E9.5 to label Pax7+ cells for lineage tracing and collected at later time points for analysis. The YFP-labelled cells which belonged to the Pax7 lineage were enriched by fluorescence-activated cell sorting (FACS) and subject to single-cell RNA profiling. We observed that a subpopulation of cells differentiated into the myogenic lineage, showing Myf5 expression as early as E12.5, whereas the rest of the population was fibroblast-like and appeared to be the early stage of the adipogenic and dermal lineages. Cells at E14.5 had distinct myogenic populations that expressed Myod1 and Myog; we also identified other populations with Ebf2 or Twist2 expression, which could belong to adipogenic or dermal lineages, respectively. Cell surface markers were also found for each specific lineage, providing insights in sorting strategy for lineage-of-interest for further functional evaluation. Adipogenic lineage was successfully sorted with a combination of Pdgfra and Thy1 antibodies. In addition, we found that upregulation of Wnt signaling pathway activity is dynamically regulated in dermal lineage. Finally, transcription factors that could potentially drive, or reprogram cell fate, were identified at different developmental time points.\n\nSummary statementInvestigation of Pax7 lineage transcriptomic profile at single-cell level identified multiple cell types, fate commitment time point, surface markers, transcription factors and signaling pathways that determine cell fate.

developmental biology↗

bioRxiv2019

HSA+ immature cardiomyocytes persist in the adult heart and expand after ischemic injury

The assessment of the regenerative capacity of the heart has been compromised by the lack of surface signatures to characterize cardiomyocytes. Here, combined multiparametric surface marker analysis with single cell transcriptional profiling and in vivo transplantation, identify the main fetal cardiac populations and their progenitors. We found that cardiomyocytes at different stages of differentiation co-exist during development. We identified a population of immature HSA/CD24+ cardiomyocytes that persists throughout life and that, unlike other cardiomyocyte subsets, actively proliferates up to one week of age and engraft cardiac tissue upon transplantation. In adult heart HSA/CD24+ cardiomyocytes appear as mononucleated cells that cycle and increase in frequency after infarction. Our work identified cell surface signatures that allow the prospective isolation of cardiomyocytes at any developmental stage and the detection of adult cardiomyocytes poised for activation in response to ischemic stimuli. This work opens new perspectives in the understanding and treatment of heart pathologies.

developmental biology↗