Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA356839 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5092030.fastq.gz | Fastqsanger.gz | |||
| SRR5092040.fastq.gz | Fastqsanger.gz | |||
| SRR5092031.fastq.gz | Fastqsanger.gz | |||
| SRR5092041.fastq.gz | Fastqsanger.gz | |||
| SRR5092032.fastq.gz | Fastqsanger.gz |
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Project description:Mammalian cardiomyocytes lose the ability to proliferate shortly after birth. This accounts for the limited regeneration capacity of the mammalian heart. A characteristic feature of growth arrested cardiomyocytes is binucleation, but the molecular mechanisms are not well understood. In rodents, binucleation of cardiomyocytes starts after birth and occurs through incomplete cytokinesis. Here we demonstrate an important and unexpected role of GAS2L3, a recently identified actin and tubulin binding protein, for cardiomyocyte cytokinesis during heart development in mice. Mice deficient in GAS2L3 die shortly after birth due to dilated cardiomyopathy. Cardiomyocyte-specific deletion of GAS2L3 confirmed that the phenotype resulted from the loss of GAS2L3 in cardiomyocytes. We show that a deficiency in GAS2L3 leads to a strong reduction in cardiomyocyte numbers due to reduced proliferation. In addition, the loss of Gas2l3 resulted in premature binucleation of cardiomyocytes and in induction of a p53-transcriptional program including the cell cycle inhibitor p21. Collectively, these data identify an important role for GAS2L3 in cardiomyocyte cytokinesis during development.
2017-06-28 | GSE91078 | GEO
Project description:Noncompaction cardiomyopathy is a common congenital cardiomyopathy associated with a deficiency of ventricular cardiomyocytes and impaired pump function. The genetic basis and underlying mechanisms of this disorder remain elusive. Polyploidization is an intrinsic feature of mammalian cardiomyocytes, which occurs shortly after birth and is accompanied by cardiomyocyte cell cycle arrest. We show that genetic deletion of the RNA binding protein with multiple splicing (Rbpms) in mice results in premature onset of cardiomyocyte polyploidization (binucleation) and consequent noncompaction cardiomyopathy. A similar blockade to cytokinesis occurs in human iPSC-derived cardiomyocytes with RBPMS gene deletion. Paired-end RNA sequencing analysis revealed that Rbpms plays an essential role in RNA splicing and mediates isoform switching from the short to the long form of Pdlim5, a heart-specific LIM domain protein that connects the sarcomere with various signaling proteins during heart development. The loss of Rbpms leads to abnormal accumulation of short Pdlim5 isoforms that disrupt cardiomyocyte cytokinesis. Our results link premature cardiomyocyte binucleation to noncompaction cardiomyopathy and highlight the central role of Rbpms in this process.
2022-02-17 | GSE182949 | GEO
Project description:Heart muscle cells, cardiomyocytes, are highly differentiated cells that usually do not proliferate . During the non-proliferative state, extracellular signals control cardiomyocyte contractile function. However, during development and regeneration, cardiomyocytes enter the cell cycle and divide. It is unknown how cardiomyocytes modify their intracellular signaling to direct the cell cycle program. Here, we show that the nuclear lamina protein Lamin B2 (Lmnb2) regulates cardiomyocyte cell cycle activity using a gatekeeper mechanism. We identified Lmnb2 as a candidate for regulating intracellular signaling with deep transcriptional profiling of single cardiomyocytes. Lmnb2 was sufficient and necessary for cardiomyocyte cycling in the presence of serum. Lmnb2 increased the nucleoporin NUP98 and permeability of the nuclear membrane for phosphorylated ERK1/2. In vivo, the Lmnb2 gene was required for cardiomyocyte cell cycle activity during development. Increasing the expression of Lmnb2 in neonatal mice promoted cardiomyocyte M-phase and cytokinesis. LmnB2 gene transfer in neonatal mice that received a myocardial injury increased cardiomyocyte division and myocardial function in the injury border zone, indicating that the regenerated cardiomyocytes were functionally integrated. We propose a gatekeeper function of Lmnb2 that can be targeted to increase cardiomyocyte regeneration without the administration of exogenous growth factors.
2020-02-28 | GSE108360 | GEO
Project description:CCBE1 is a secreted extracellular matrix protein expressed by epicardial cells but its role during epicardial development was still unknown.Using a Ccbe1 knockout (KO) mouse model, we observed that loss of CCBE1 leads to congenital heart defects including thinner and hyper-trabeculated ventricular myocardium. In addition, Ccbe1 mutant hearts displayed reduced proliferation of cardiomyocyte and epicardial cells. RNA-seq data of CCBE1 KO and WT murine hearts indicated deregulation of genes associated with development and morphogenesis including the epithelial-to-mesenchymal transition.
2022-10-23 | E-MTAB-12217 | biostudies-arrayexpress
Project description:Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development
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Project description:Background: The protein kinase PKN2 is required for embryonic development, and PKN2 knockout mice die as a result of failure in expansion of mesoderm tissues, cardiac development and neural tube closure. In the adult, cardiomyocyte PKN2 and PKN1 (in combination) are required for cardiac adaptation to pressure-overload. The role of PKN2 in contractile cardiomyocytes during development and its role in the adult heart remain to be fully established. Methods: We used mice with cardiomyocyte-directed knockout of PKN2 or global PKN2 haploinsufficiency. Cardiac function and dimensions were assessed with high resolution episcopic microscopy, MRI, micro-CT and echocardiography. Biochemical and histological changes were assessed. Results: Cardiomyocyte-directed PKN2 knockout embryos displayed striking abnormalities in the compact myocardium, with frequent myocardial clefts and diverticula, ventricular septal defects and abnormal heart shape. The sub-Mendelian homozygous knockout survivors developed cardiac failure. RNASeq data showed upregulation of PKN2 in patients with dilated cardiomyopathy, suggesting an involvement in adult heart disease. Given the rarity of homozygous survivors with cardiomyocyte-specific deletion of PKN2, this was explored using mice with constitutive heterozygous PKN2 knockout. Cardiac hypertrophy resulting from hypertension induced by angiotensin II was reduced in haploinsufficient PKN2 mice relative to wild-type littermates, with suppression of cardiomyocyte hypertrophy and cardiac fibrosis. Conclusions: Cardiomyocyte PKN2 is essential for heart development and formation of compact myocardium, and is also required for cardiac hypertrophy in hypertension. Thus, PKN signalling may offer therapeutic options for managing congenital and adult heart diseases.
2022-06-24 | GSE206779 | GEO
Project description:Epigenetic regulation of heart development remains incompletely understood. Here we show that lysine-specific demethylase 1 (LSD1), a histone demethylase, critically controls cardiomyocyte proliferation during heart development. Cardiomyocyte-specific deletion of Lsd1 in mice inhibited cardiomyocyte proliferation, causing severe growth defect of embryonic and neonatal heart. In vivo RNA-seq and in vitro functional studies identified Cend1, a cell cycle repressor, as a target suppressed by LSD1. Loss of Lsd1 resulted in elevated Cend1 transcription associated with increased active histone mark H3K4me2 at the Cend1 promoter regions. Cend1 knockdown fully relieved the cell cycle arrest and proliferation defect caused by LSD1 inhibition in primary rat cardiomyocytes. Consistently, genetic deletion of Cend1 rescued cardiomyocyte proliferation defect and embryonic lethality in Lsd1 null embryos. Mechanistically, LSD1 promoted cardiomyocyte cycling and proliferation via CEND1-mediated suppression of p53 pathway. In line with the observations in mice, LSD1 promoted the cell cycle of cardiomyocytes derived from human-induced pluripotent stem cells by repressing CEND1-p53 axis. Together, these findings reveal an epigenetic regulatory mechanism consisting of the LSD1-CEND1-p53 axis that controls cardiomyocyte proliferation essential for murine heart development.
2023-10-30 | GSE244414 | GEO
Project description:Proliferation of heart muscle cells (cardiomyocytes) is the basis for heart development and regeneration. In mammals, cardiomyocytes become binucleated, which is thought to limit their proliferative capacity, but mechanisms are unknown. Here, we show the detailed mechanisms of formation of binucleated cardiomyocytes and how these mechanisms are dysregulated in congenital heart disease (CHD). Cardiomyocytes become binucleated by failing the last stage of cytokinesis, abscission. We identified the underlying molecular mechanism with single-cell transcriptional profiling, which showed repression of the cytokinesis gene Ect2, a Rho-guanine-nucleotide exchange factor. Inactivating Ect2 tripled the proportion of binucleated cardiomyocytes and reduced the number of cardiomyocytes by 34% in newborn mice, which was lethal. Cardiomyocyte-specific overexpression of Ect2 in transgenic mice decreased cytokinesis failure. We demonstrate that the Ect2 gene is regulated by the Hippo tumor suppressor pathway, and upstream of that, by β-adrenergic receptor signaling. In neonatal mice, stimulating β-adrenergic signaling pathway output with forskolin decreased the number of cardiomyocytes, and administration of β-blockers increased the number of cardiomyocytes. Finally, we show that patients with tetralogy of Fallot with pulmonary stenosis (ToF/PS), a common type of CHD, develop a 2.2-fold increase in bi- and multi-nucleated cardiomyocytes. Using in vivo labeling of one ToF/PS patient with 15N-thymidine, followed by imaging mass spectrometry, we demonstrate that this increase happens after birth. Organotypic cultures of myocardium from infants with ToF/PS showed that cardiomyocyte binucleation could be reduced with β-blockers. These results demonstrate how cardiomyocyte proliferation stops and provide the basis for new therapeutic strategies to increase cardiomyocyte proliferation in patients with CHD.
2019-09-30 | GSE108359 | GEO
Project description:Genome-wide cardiac gene expression analysis of mice with cardiomyocyte-specific deletion of Dnmt3a and Dnmt3b
| PRJNA282965 | ENA
Project description:Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions
| PRJNA371776 | ENA