uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier
FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
Osped San Raffaele, Mol Neurobiol Lab, Div Neurosci, Milan, Italy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Show others and affiliations
2019 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, no 4, p. 511-525Article in journal (Refereed) Published
Abstract [en]

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/β-catenin signaling is responsible for the early phases of brain vascularization and BBB differentiation. However, this signal declines after birth, and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown.

Objective: Sox17 (SRY [sex-determining region Y]-box 17) constitutes a major downstream target of Wnt/β-catenin in endothelial cells and regulates arterial differentiation. In the present article, we asked whether Sox17 may act downstream of Wnt/β-catenin in inducing BBB differentiation and maintenance.

Methods and Results: Using reporter mice and nuclear staining of Sox17 and β-catenin, we report that although β-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 sequencing analysis of gene expression of brain endothelial cells has identified members of the Wnt/β-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/β-catenin signaling, and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the β-catenin destruction complex or expression of a degradation-resistant β-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/β-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.

Place, publisher, year, edition, pages
2019. Vol. 124, no 4, p. 511-525
Keywords [en]
blood-brain barrier, endothelial cells, permeability, stroke, Wnt/beta-catenin
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-378993DOI: 10.1161/CIRCRESAHA.118.313316ISI: 000458887600025PubMedID: 30591003OAI: oai:DiVA.org:uu-378993DiVA, id: diva2:1297185
Funder
EU, European Research Council, 742922Swedish Research CouncilKnut and Alice Wallenberg FoundationGerman Research Foundation (DFG), FOR2325Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved

Open Access in DiVA

fulltext(13854 kB)49 downloads
File information
File name FULLTEXT01.pdfFile size 13854 kBChecksum SHA-512
52d6ee07210bd52399e9609863f45ae6626955d9fab7b3abd0b151acff6d96598a4ca0c2a39350879b703f51b959540b2e7dfa0ae07c4067a058f02e3ba9aeee
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Conze, Lei LiuCunha, Sara I.Claesson-Welsh, LenaMagnusson, PeetraDejana, Elisabetta

Search in DiVA

By author/editor
Conze, Lei LiuCunha, Sara I.Claesson-Welsh, LenaMagnusson, PeetraDejana, Elisabetta
By organisation
Vascular Biology
In the same journal
Circulation Research
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 49 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 139 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf