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Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endodermal gene regulatory network

ABSTRACT: Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endodermal gene regulatory network

PROVIDER: PRJNA625510 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11549523.fastq.gz	Fastqsanger.gz
	SRR11549524.fastq.gz	Fastqsanger.gz
	SRR11549525.fastq.gz	Fastqsanger.gz
	SRR11549526.fastq.gz	Fastqsanger.gz
	SRR11549527.fastq.gz	Fastqsanger.gz

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Project description:Rationale. The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/b-catenin signaling is responsible for the early phases of brain vascularization and blood-brain barrier differentiation. However, this signal declines after birth and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown. Objective. Sox17 constitutes a major downstream target of Wnt/b-catenin in endothelial cells and regulates arterial differentiation. In the present paper, we asked whether Sox17 may act downstream of Wnt/b-catenin in inducing BBB differentiation and maintenance. Methods and Results. Using reporter mice and nuclear staining of Sox17 and b-catenin, we report that while b-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult. Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation. The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo, and progressively declines after birth. In search of Sox17 mechanism of action, RNA-Seq analysis of gene expression of brain endothelial cells has identified members of the Wnt/b-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/b-catenin signaling and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the b-catenin destruction complex or expression of a degradation-resistant b-catenin mutant, prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17. Conclusions. Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB and they underline the strict reciprocal tuning of this transcription factor and Wnt/b-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.

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Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endodermal gene regulatory network

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