Endothelial progenitor migration and differentiation is regulated by distinct transcriptional effectors of Cloche/Npas4l
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA700672 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13660515_1.fastq.gz | Fastqsanger.gz | |||
| SRR13660515_2.fastq.gz | Fastqsanger.gz | |||
| SRR13660516_1.fastq.gz | Fastqsanger.gz | |||
| SRR13660516_2.fastq.gz | Fastqsanger.gz |
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Project description:Embryonic cells including endothelial progenitors undergo extensive migration and differentiation events; however, whether and how these processes are interrelated remains unclear. The transcription factor Npas4l is necessary for endothelial specification in zebrafish by inducing the expression of the transcription factor genes etsrp, tal1 and lmo2. We generated a knock-in reporter in the npas4l locus to visualize endothelial progenitors and their derivatives in wild-type and mutant embryos. We find that in npas4l mutants, npas4l reporter expressing cells do not migrate to the midline and instead contribute to skeletal muscle and pronephric tubules. Investigating the Npas4l transcriptional effectors, we find that npas4l reporter expressing cells in tal1 mutants fail to migrate while those in etsrp mutants migrate but fail to differentiate. In lmo2 mutants, npas4l reporter expressing cells migrate and differentiate, but many express pronephric tubule markers. Altogether, these data reveal the complex regulation of endothelial progenitor migration, differentiation and fate restriction.
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Project description:The endocardium plays important roles in the development and function of the vertebrate heart; however, few molecular markers of this tissue have been identified and little is known about what regulates its differentiation. Here, we describe the Gt(SAGFF27C); Tg(4xUAS:egfp) line as a marker of endocardial development in zebrafish. Transcriptomic comparison between endocardium and pan-endothelium confirms molecular distinction between these populations and time-course analysis suggests differentiation as early as eight somites. To investigate what regulates endocardial identity, we employed npas4l, etv2 and scl loss-of-function models. Endocardial expression is lost in npas4l mutants, significantly reduced in etv2 mutants and only modestly affected upon scl loss-of-function. Bmp signalling was also examined: overactivation of Bmp signalling increased endocardial expression, whereas Bmp inhibition decreased expression. Finally, epistasis experiments showed that overactivation of Bmp signalling was incapable of restoring endocardial expression in etv2 mutants. By contrast, overexpression of either npas4l or etv2 was sufficient to rescue endocardial expression upon Bmp inhibition. Together, these results describe the differentiation of the endocardium, distinct from vasculature, and place npas4l and etv2 downstream of Bmp signalling in regulating its differentiation.
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Project description:The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification in vertebrates remains incomplete. cloche/npas4l mutants have broadly been used as an avascular model in zebrafish, but little is known about the molecular mechanism of action of Npas4l. Here, to identify the direct and indirect target genes of this transcription factor, we combined complementary genome-wide approaches, including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicate that Npas4l functions as a master regulator by directly inducing a wave of transcription factor genes crucial for hematoendothelial specification in vertebrates, including etv2, tal1, and lmo2. We identified additional target genes acting downstream of npas4l and investigated the function of a subset of them using CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel role for tspan18b in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to investigate novel genes with a potential role in vascular development and EC fate determination in vertebrates.
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Project description:The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification in vertebrates remains incomplete. cloche/npas4l mutants have broadly been used as an avascular model in zebrafish, but little is known about the molecular mechanism of action of Npas4l. Here, to identify the direct and indirect target genes of this transcription factor, we combined complementary genome-wide approaches, including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicate that Npas4l functions as a master regulator by directly inducing a wave of transcription factor genes crucial for hematoendothelial specification in vertebrates, including etv2, tal1, and lmo2. We identified additional target genes acting downstream of npas4l and investigated the function of a subset of them using CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel role for tspan18b in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to investigate novel genes with a potential role in vascular development and EC fate determination in vertebrates.
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