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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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 955 records · Page 53Linked to original sources

bioRxiv2018

3D Tissue elongation via ECM stiffness-cued junctional remodeling

Organs are sculpted by extracellular as well as cell-intrinsic forces, but how collective cell dynamics are orchestrated in response to microenvironmental cues is poorly understood. Here we apply advanced image analysis to reveal ECM-responsive cell behaviors that drive elongation of the Drosophila follicle, a model 3D system in which basement membrane stiffness instructs tissue morphogenesis. Through in toto morphometric analyses of WT and round egg mutants, we find that neither changes in average cell shape nor oriented cell division are required for appropriate organ shape. Instead, a major element is a reorientation of elongated cells at the follicle anterior. Polarized reorientation is regulated by mechanical cues from the basement membrane, which are transduced by the Src tyrosine kinase to alter junctional E-cadherin trafficking. This mechanosensitive cellular behavior represents a conserved mechanism that can elongate edgeless tubular epithelia in a process distinct from those that elongate bounded, planar epithelia.

developmental biology↗

bioRxiv2018

Effects of the maternal factor Zelda on zygotic enhancer activity in the Drosophila embryo

The maternal factor Zelda is broadly bound to zygotic enhancers during early fly embryogenesis, and has been shown to be important for the expression of a large number of genes. However, its function remains poorly understood. Here, we carried out detailed analysis of the functional role of Zelda on the activities of a group of enhancers that drive patterned gene expression along the anterior -posterior axis. We found that among these enhancers, only one lost its activity entirely when all its Zelda bind sites were mutated. For all others, mutations of all of their Zelda binding sites only had limited effect, which varied temporally and spatially. These results suggest that Zld may exert a quantitative effect on a broad range of enhancers, which presumably is critical to generate highly diverse spatial and temporal expression patterns for different genes in the developmental gene network in fly embryo. Lastly, we found that the observed effect of Zelda site mutations was much stronger when a mutant enhancer was tested using a BAC based reporter construct than a simple reporter construct, suggesting that the effect of Zld is dependent on chromatin environment.

developmental biology↗

bioRxiv2018

Single-cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development

The mouse embryo is the canonical model for mammalian preimplantation development. Recent advances in single-cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single-cell RNA-seq. Zygotic genome activation correlates with the presence of Polycomb Repressive Complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species-, stage- and lineage-specific. The pluripotency network in the primate epiblast lacks certain regulators operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and nonhuman primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of preimplantation development and underscores the molecular adaptability of early mammalian embryogenesis.

developmental biology↗

bioRxiv2018

Alterations in sperm long RNA contribute to the epigenetic inheritance of the effects of postnatal trauma

Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells 1,2. Initial evidence suggested that sperm RNA is causally linked 2,3 to the transmission of symptoms induced by traumatic experiences. Here we show that alterations in long RNA in sperm contribute to the inheritance of specific trauma symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal trauma recapitulates the effects on food intake, glucose response to insulin and risk-taking in adulthood whereas the small RNA fraction alters body weight and behavioral despair. Alterations in long RNA are maintained after fertilization, suggesting a direct link between sperm and embryo RNA.

developmental biology↗

bioRxiv2018

Assessing placental maturity through histological and transcriptomic analyses in idiopathic spontaneous preterm birth

Preterm birth (PTB) is leading contributor to infant death in the United States and globally, yet the underlying mechanistic causes are not well understood. Histopathological studies of preterm birth suggest advanced villous maturity may have a role in idiopathic spontaneous preterm birth (isPTB). To better understand pathological and molecular basis of isPTB, we compared placental villous transcriptomes from carefully phenotyped cohorts of PTB due to infection or isPTB between 28-36 weeks gestation and healthy term placentasu. Transcriptomic analyses revealed a unique expression signature for isPTB distinct from the age-matched controls that were delivered prematurely due to infection. This signature included the upregulation of three IGF binding proteins (IGFBP1, IGFBP2, and IGFBP6), supporting a role for aberrant IGF signaling in isPTB. However, within the isPTB expression signature, we detected secondary signature of inflammatory markers including TNC, C3, CFH, and C1R, which have been associated with placental maturity. In contrast, the expression signature of the gestational age-matched infected samples included upregulation of proliferative genes along with cell cycling and mitosis pathways. Together, these data suggest an isPTB molecular signature of placental hypermaturity, likely contributing to the premature activation of inflammatory pathways associated with birth and providing a molecular basis for idiopathic spontaneous birth.

developmental biology↗

bioRxiv2018

Multi-modal regulation of C. elegans hermaphrodite spermatogenesis by the GLD-1-FOG-2 complex

Proper germ cell sex determination in Caenorhabditis nematodes requires a network of RNA-binding proteins (RBPs) and their target mRNAs. In some species, changes in this network enabled limited XX spermatogenesis, and thus self-fertility. In C. elegans, one of these selfing species, the global sex-determining gene tra-2 is regulated in germ cells by a conserved RBP, GLD-1, via the 3 untranslated region (3UTR) of its transcript. A C. elegans-specific GLD-1 cofactor, FOG-2, is also required for hermaphrodite sperm fate, but how it modifies GLD-1 function is unknown. Germline feminization in gld-1 and fog-2 null mutants has been interpreted as due to cell-autonomous elevation of TRA-2 translation. Consistent with the proposed role of FOG-2 in translational control, the abundance of nearly all GLD-1 target mRNAs (including tra-2) is unchanged in fog-2 mutants. Epitope tagging reveals abundant TRA-2 expression in somatic tissues, but an undetectably low level in wild-type germ cells. Loss of gld-1 function elevates germline TRA-2 expression to detectable levels, but loss of fog-2 function does not. A simple quantitative model of tra-2 activity constrained by these results can successfully sort genotypes into normal or feminized groups. Surprisingly, fog-2 and gld-1 activity enable the sperm fate even when GLD-1 cannot bind to the tra-2 3 UTR. This suggests the GLD-1-FOG-2 complex regulates uncharacterized sites within tra-2, or other mRNA targets. Finally, we quantify the RNA-binding capacities of dominant missense alleles of GLD-1 that act genetically as \"hyperrepressors\" of tra-2 activity. These variants bind RNA more weakly in vitro than does wild-type GLD-1. These results indicate that gld-1 and fog-2 regulate germline sex via multiple interactions, and that our understanding of the control and evolution of germ cell sex determination in the C. elegans hermaphrodite is far from complete.

developmental biology↗

bioRxiv2018

Foxp1 controls neural stem cell competence and bias towards deep layer cortical fate.

SUMMARYThe laminar architecture of the mammalian neocortex depends on the orderly generation of distinct neuronal subtypes by apical radial glia (aRG) during embryogenesis. We identify critical roles for Foxp1 in maintaining RG identity and gating the temporal competency for early neurogenesis. High levels of Foxp1 are associated with early aRG and are required to promote proliferation and influence cell division symmetry, favoring aRG expansion and production of early born neurons. The potent pro-progenitor functions of Foxp1 are revealed through its ability to preserve a population of cells with aRG identity throughout development and extend the early neurogenic period into postnatal life. Foxp1 further promotes the formation of cells resembling basal RG (bRG), a progenitor group implicated in the increased size and complexity of the human cortex. Consistent with this role, we show that FOXP1 is associated with the initial formation and expansion of bRG during human corticogenesis.\n\nHIGHLIGHTSO_LIFoxp1 is transiently expressed by aRG during the early phase of corticogenesis\nC_LIO_LIFoxp1 promotes self-renewing vertical cell divisions and aRG maintenance\nC_LIO_LIFoxp1 gates the time window of deep layer neurogenesis\nC_LIO_LIEctopic Foxp1 expression can elicit bRG formation\nC_LI

developmental biology↗

bioRxiv2018

Fndc3a (Fibronectin Domain Containing Protein 3A) influences median fin fold development and caudal fin regeneration in zebrafish by ECM alteration.

Summary statementWe investigated potential functions of Fndc3a during caudal fin development and regeneration in zebrafish. Reduced function interferes with correct epidermal cells structure and implies a role during vertebrate extremity development.\n\nAbstractInherited genetic alterations are often found to be disease-causing factors of patient phenotypes. To unravel the molecular consequences of newly identified factors functional investigations in vivo are eminent. We investigated molecular functions of FNDC3A (Fibronectin Domain Containing Protein 3A; HUGO), a novel candidate gene for split-hand/foot malformations (SHFM) in humans, by utilizing zebrafish (Danio rerio) as a vertebrate model. Patients with congenital SHFM display prominent limb malformations, which are caused by disturbance of limb development due to defects in apical ectodermal ridge (AER) establishment and maintenance. Initial gene expression and protein localization studies clarified the presence of fndc3a in developing and regenerating fins of zebrafish. For functional studies we established a hypomorphic fndc3a mutant line (fndc3awue1/wue1) via CRISPR/Cas9, exhibiting phenotypic malformations and changed gene expression patterns during early stages of median fin fold development. Furthermore, fndc3awue1/wue1 mutants display abnormal collagen localization, actinotrichia breakup and cellular defects in epidermal cells during caudal fin development. The observed effects are only temporary and later result in rather normal fin development in adults. In accordance with early fin development, proper caudal fin regeneration in adult fndc3awue1/wue1 mutants is hampered by interference with actinotrichia formation and epidermal cell abnormalities. Investigation of cellular matrix formation implied that loss of ECM structure is a common cause for both phenotypes. Our results thereby provide a molecular link between Fndc3a function during both developmental processes in zebrafish and foreshadow Fndc3a as a novel temporal regulator of epidermal cell properties during extremity development in vertebrates.

developmental biology↗

bioRxiv2018

tudor-domain containing protein 5-prime promotes male sexual identity in the Drosophila germline and is repressed in females by Sex lethal

For sexually reproducing organisms, production of male or female gametes depends on specifying the correct sexual identity in the germline. In D. melanogaster, Sex lethal (Sxl) is the key gene that controls sex determination in both the soma and the germline, but how it does so in the germline is unknown, other than that it is different than in the soma. We conducted an RNA expression profiling experiment to identify direct and indirect germline targets of Sxl specifically in the undifferentiated germline. We find that, in these cells, Sxl loss does not lead to a global masculinization observed at the whole-genome level. In contrast, Sxl appears to affect a discrete set of genes required in the male germline, such as Phf7. We also identify tudor domain containing protein 5-prime (tdrd5p) as a target for Sxl regulation that is important for male germline identity. tdrd5p is repressed by Sxl in female germ cells, but is highly expressed in male germ cells where it promotes proper male fertility and germline differentiation. Additionally, Tdrd5p localizes to cytoplasmic granules with some characteristics of RNA Processing (P-) Bodies, suggesting that it promotes male identity in the germline by regulating post-transcriptional gene expression.\n\nAuthor summaryLike humans, all sexually reproducing organisms require gametes to reproduce. Gametes are made by specialized cells called germ cells, which must have the correct sexual identity information to properly make sperm or eggs. In fruit flies, germ cell sexual identity is controlled by the RNA-binding protein Sxl, which is expressed only in females. To better understand how Sxl promotes female identity, we conducted an RNA expression profiling experiment to identify genes whose expression changes in response to the loss of Sxl from germ cells. Here, we identify tudor domain containing protein 5-prime (tdrd5p), which is expressed 17-fold higher in ovaries lacking Sxl compared to control ovaries. Additionally, tdrd5p plays an important role in males as male flies that are mutant for this gene cannot make sperm properly and thus are less fertile. Moreover, we find that tdrd5p promotes male identity in the germline, as several experiments show that it can shift the germ cell developmental program from female to male. This study tells us that Sxl promotes female identity in germ cells by repressing genes, like tdrd5p, that promote male identity. Future studies into the function of tdrd5p will provide mechanistic insight into how this gene promotes male identity.

developmental biology↗

bioRxiv2018

Are these cardiomyocytes? Protocol development reveals impact of sample preparation on the accuracy of identifying cardiomyocytes by flow cytometry

Modern differentiation protocols enable efficient, yet imperfect, differentiation of human pluripotent stem cells into cardiomyocytes (hPSC-CM). As the number of laboratories and studies implementing this technology expands, the accurate assessment of cell identity in differentiation cultures is paramount to well-defined studies that can be replicated among laboratories. While flow cytometry is apt for routine assessment, a standardized protocol for assessing cardiomyocyte identity in hPSC-CM cultures has not yet been established. To address this gap, the current study leveraged targeted mass spectrometry to confirm the presence of troponin proteins in hPSC-CM and systematically evaluated multiple anti-troponin antibodies and sample preparation protocols for their suitability in assessing cardiomyocyte identity. Results demonstrate challenges of interpreting data generated by published methods and informed the development of a robust protocol for routine assessment of hPSC-CM. Overall, the new data, workflow for evaluating fit-for-purpose use of antibodies, and standardized protocol described here should benefit investigators new to this field as well as those with expertise in hPSC-CM differentiation.

developmental biology↗

bioRxiv2018

Hydraulic control of embryo size, tissue shape and cell fate

Size control is fundamental in tissue development and homeostasis1,2. While the role of cell proliferation in this process has been widely studied3, the mechanisms of organ size control and how it impacts cell fates remain elusive. Here, we use mouse blastocyst development as a model to unravel a key role of fluid-filled lumen in embryonic size control and cell fate specification. We find that during blastocyst expansion, there is a two-fold increase in the pressure of the lumen that translates into a concomitant increase in the cortical tension of trophectoderm (TE) cells lining the lumen. Increased cortical tension leads to vinculin mechanosensing and maturation of the functional tight junctions, thereby establishing a positive feedback loop to accommodate lumenal growth. However, when the cortical tension reaches a critical threshold, cell-cell adhesion cannot be sustained, and mitotic entry leads to a rupture of TE epithelium, fluid leakage and collapse of the blastocyst cavity. A simple theory of hydraulically-gated oscillations that integrates these feedback interactions recapitulates the evolution of cavity size and predicts the scaling of embryonic size with the tissue volume. Our theory further predicts that reduced cortical tension or disrupted tight junctions, and increased tissue stiffness lead to smaller embryonic size. These predictions are verified experimentally by embryological, pharmacological and genetic manipulations of the embryos. Remarkably, these changes to lumenal size, without a change in the tissue volume, lead to alteration of tissue architecture and cell fate. Overall, our study reveals how lumenal pressure and tissue mechanics control embryonic size at the tissue scale, that in turn couples to cell position and fate at the cellular scale.

developmental biology↗

bioRxiv2018

Maintaining trunk neural crest cells as crestospheres

Neural crest cells have broad migratory and differentiative ability that differs according to their axial level of origin. However, their transient nature has limited understanding of their stem cell and self-renewal properties. While an in vitro culture method has made it possible to maintain cranial neural crest cells as self-renewing multipotent crestospheres (Kerosuo et al., 2015), these same conditions failed to preserve trunk neural crest in a stem-like state. Here we optimize culture conditions for maintenance of trunk crestospheres, comprised of both neural crest stem and progenitor cells. Trunk crestospheres display elevated expression of neural crest cell markers as compared to those characteristic of neural tube or mesodermal fates. Moreover, trunk crestospheres have increased expression of trunk-related markers as compared to cranial genes. Finally, we use lentiviral transduction as a tool to manipulate gene expression in trunk crestospheres. Taken together, this method enables long-term in vitro maintenance and manipulation of trunk neural crest cells in a premigratory stem or early progenitor state to probe the mechanisms underlying their stemness and lineage decisions.\n\nHighlightsO_LITrunk-derived multipotent neural crest stem cells can be cultured as crestospheres\nC_LIO_LITrunk-derived crestospheres require different conditions than cranial\nC_LIO_LITrunk crestospheres consist of neural crest stem and progenitor cells\nC_LIO_LITrunk crestospheres can be efficiently transduced using lentiviral vectors\nC_LI

developmental biology↗

bioRxiv2018

Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition

miR-203 is a tumor-suppressor microRNA with known functions in cancer metastasis. Here, we explore its normal developmental role in the context of neural crest development. As neural crest cells undergo an epithelial-to-mesenchymal transition to emigrate from the neural tube, miR-203 displays a reciprocal expression pattern with key regulators of neural crest delamination, Phf12 and Snail2, and interacts with their 3UTRs. Ectopic maintenance of miR-203 inhibits neural crest migration, whereas its functional inhibition using a \"sponge\" vector promotes premature neural crest delamination. Bisulfite sequencing further shows that epigenetic repression of miR-203 is mediated by the de novo DNA methyltransferase DNMT3B, whose recruitment to regulatory regions on the miR-203 locus is directed by SNAIL2 in a negative feedback loop. These findings reveal an important role for miR-203 in an epigenetic-microRNA regulatory network that influences the timing of neural crest delamination.\n\nSummary statementThe EMT is a highly conserved process, involving similar levels of regulation in both neural crest and cancer cells. Our work shows an epigenetic-miRNA-gene regulatory circuit, conserved in cancer, which controls the timing of neural crest EMT as well.

developmental biology↗

bioRxiv2018

The Warburg effect and lactate signaling augment Fgf signaling to promote sensory-neural development in the otic vesicle

Recent studies indicate that many developing tissues modify glycolysis to favor lactate synthesis, but how this promotes development is unclear. Using forward and reverse genetics in zebrafish, we show that disrupting the glycolytic gene phosphoglycerate kinase-1 (pgk1) impairs Fgf-dependent development of hair cells and neurons in the otic vesicle and other neurons in the CNS/PNS. Focusing on the otic vesicle, we found that Fgf signaling underperforms in pgk1-/- mutants even when Fgf is transiently overexpressed. Wild-type embryos treated with drugs that block synthesis or secretion of lactate mimic the pgk1-/- phenotype, whereas pgk1-/- mutants are rescued by treatment with exogenous lactate. Lactate treatment of wild-type embryos elevates expression of Etv5b/Erm even when Fgf signaling is blocked. Thus, by raising steady-state levels of Etv5b (a critical effector of the Fgf pathway), lactate renders cells more responsive to dynamic changes in Fgf signaling required by many developing tissues.

developmental biology↗

bioRxiv2018

Nell2 regulates the contralateral-versus-ipsilateral visual projection as a layer-specific positional cue

SUMMARY STATEMENTNell2 is an ipsilateral layer-specific axon guidance cue in the visual thalamus and contributes to establishment of the eye-specific retinogeniculate projection by specifically inhibiting contralateral retinal axons.\n\nABSTRACTIn mammals with binocular vision, retinal ganglion cell (RGC) axons from each eye project to eye-specific layers in the contralateral and ipsilateral dorsal lateral geniculate nucleus (dLGN). Although layer-specific axon guidance cues that discriminate contralateral and ipsilateral RGC axons have long been postulated as a key mechanism for development of the eye-specificretinogeniculate projection, the molecular nature of such cues has remained elusive. Here we show that the extracellular glycoprotein Nell2 (also known as Nel) is expressed in the dorsomedial region of the dLGN, which corresponds to the layer receiving ipsilateral RGC axons. In Nell2 mutant mice, contralateral RGC axons invaded the ipsilateral layer of the dLGN, and ipsilateral axons terminated in partially fragmented patches, forming a mosaic pattern of contralateral and ipsilateral axon termination zones. In vitro, Nell2 exerted inhibitory effects on contralateral, but not ipsilateral, RGC axons. These results provide evidence that Nell2 acts as a layer-specific positional label in the dLGN that discriminates contralateral and ipsilateral RGC axons, and that it plays essential roles in establishment of the eye-specific projection patterns in the retinogeniculate system.

developmental biology↗

bioRxiv2018

Delayed aneuploidy stress response of neural stem cells impairs adult lifespan in flies

SummaryStudying aneuploidy during organism development has strong limitations, as chronic mitotic perturbations used to generate aneuploidy result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity.\n\nLarvae challenged with aneuploidy hatch into adults with severe motor defects shortening their lifespan. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, complex array of karyotypes and cellular abnormalities. Notably, when other brain cell-lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed, indicating that stemness state confers resistance to aneuploidy. Sparing solely the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult lifespan, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.\n\nHighlightsO_LIReversible depletion of cohesin results in just a round or two of aberrant cell divisions, generating high levels of aneuploidy.\nC_LIO_LILarvae challenged with aneuploidy during development hatch into impaired adults.\nC_LIO_LIFew cell cycles are sufficient for chromosomal instability to emerge from a previously stable aneuploid state.\nC_LIO_LINeural stemness delays aneuploidy stress response.\nC_LIO_LIProtecting only the neural tissue from aneuploidy rescues adult abnormalities and lifespan.\nC_LI

developmental biology↗

bioRxiv2018

Dual role of Bnl/Fgf signaling in proliferation and endoreplication of Drosophila trachealadult progenitor cells

AbstractAdult progenitor cells activation is a key event in the formation of adult organs during development. The initiation of proliferation of these progenitor cells requires specific temporal signals, mostly of them still unknown. In Drosophila, formation of adult tracheal system depends on the activation of tracheal adult progenitors (tracheoblasts) of Tr4 and Tr5 tracheal metamers specific spiracular branches (SB) during the last larval stage. The mitotic activity of these tracheoblasts generate a pool of tracheal differentiated cells that migrate during pupal development along the larval trachea by the activation of the Branchless (Bnl)/Fibroblast growth factor (FGF) signaling to form the abdominal adult tracheal system. In here, we found that, in addition to migration, Bnl/FGF signaling, mediated by the transcription factor Pointed, is also required for adult progenitor cell proliferation in the SBs. Moreover, we found that tracheoblast proliferation in Tr4 and Tr5 SBs relies on the specific expression of the FGF ligand Bnl in their nearby transverse connective branches. Finally, we also show that, in absence of the transcription factor Cut (Ct), Bnl/FGF signaling induces endoreplication of differentiated tracheoblast daughter cells by in part promoting Fizzy-related (Fzr) expression. Altogether, our results suggest a dual role of Bnl/FGF signaling in tracheal adult progenitors, inducing both proliferation and endoreplication of tracheoblasts in late larval development, depending on the presence or absence of the transcription factor ct, respectively.\n\nAuthor summaryThe generation of adult organs and tissue renewal are complex processes that depend on the proliferation and posterior differentiation of undifferentiated progenitor cells in a temporal coordinated manner. Although many signals that regulate the activity of progenitor cells have been identified, the characterization of the mechanisms underlying the temporal and spatial control of such events remain unknown. The tracheal system of Drosophila, the respiratory organ, forms during embryogenesis and it is remodeled during metamorphosis from quiescent adult progenitor cells that proliferate. We have discovered that this proliferation depends on the activation of the FGF signaling as mutations that either inactivate or over-activate the pathway blocks cell division or induced over-proliferation of progenitor cells, respectively. Interestingly, we have found that the same signaling pathway also controls tracheal progenitor cells differentiation by promoting endoreplication. We found that this dual role of FGF signaling in adult progenitor cells, depends on the presence or absence of the transcription factor Cut. Altogether, our results, reveal the mechanism that control the division and differentiation of progenitor cells and open the possibility that analogous signaling pathway may play a similar role in vertebrate stem cell regulation and tumor growth.

developmental biology↗

bioRxiv2018

Myocardial Notch-Rbpj deletion does not affect heart development or function

During vertebrate cardiac development NOTCH signaling activity in the endocardium is essential for the crosstalk between endocardium and myocardium that initiates ventricular trabeculation and valve primordium formation. This crosstalk leads later to the maturation and compaction of the ventricular chambers and the morphogenesis of the cardiac valves, and its alteration may lead to disease. Although endocardial NOTCH signaling has been shown to be crucial for heart development, its physiological role in the myocardium has not been clearly established. Here we have used a genetic strategy to evaluate the role of NOTCH in myocardial development. We have inactivated the unique and ubiquitous NOTCH effector RBPJ in the early cardiomyocytes progenitors, and examined its consequences in cardiac development and function. Our results demonstrate that mice with cTnT-Cre-mediated myocardial-specific deletion of Rbpj develop to term, with homozygous mutant animals showing normal expression of cardiac development markers, and normal adult heart function. Similar observations have been obtained after Notch1 deletion with cTnT-Cre. We have also deleted Rbpj in both myocardial and endocardial progenitor cells, using the Nkx2.5-Cre driver, resulting in ventricular septal defect (VSD), double outlet right ventricle (DORV), and bicuspid aortic valve (BAV), due to NOTCH signaling abrogation in the endocardium of cardiac valves territories. Our data demonstrate that NOTCH-RBPJ inactivation in the myocardium does not affect heart development or adult cardiac function.

developmental biology↗