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Canonical WNT signaling components in vascular development and barrier formation
Yulian Zhou, … , Makoto M. Taketo, Jeremy Nathans
Yulian Zhou, … , Makoto M. Taketo, Jeremy Nathans
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(9):3825-3846. https://doi.org/10.1172/JCI76431.
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Research Article Vascular biology Article has an altmetric score of 28

Canonical WNT signaling components in vascular development and barrier formation

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Abstract

Canonical WNT signaling is required for proper vascularization of the CNS during embryonic development. Here, we used mice with targeted mutations in genes encoding canonical WNT pathway members to evaluate the exact contribution of these components in CNS vascular development and in specification of the blood-brain barrier (BBB) and blood-retina barrier (BRB). We determined that vasculature in various CNS regions is differentially sensitive to perturbations in canonical WNT signaling. The closely related WNT signaling coreceptors LDL receptor–related protein 5 (LRP5) and LRP6 had redundant functions in brain vascular development and barrier maintenance; however, loss of LRP5 alone dramatically altered development of the retinal vasculature. The BBB in the cerebellum and pons/interpeduncular nuclei was highly sensitive to decrements in canonical WNT signaling, and WNT signaling was required to maintain plasticity of barrier properties in mature CNS vasculature. Brain and retinal vascular defects resulting from ablation of Norrin/Frizzled4 signaling were ameliorated by stabilizing β-catenin, while inhibition of β-catenin–dependent transcription recapitulated the vascular development and barrier defects associated with loss of receptor, coreceptor, or ligand, indicating that Norrin/Frizzled4 signaling acts predominantly through β-catenin–dependent transcriptional regulation. Together, these data strongly support a model in which identical or nearly identical canonical WNT signaling mechanisms mediate neural tube and retinal vascularization and maintain the BBB and BRB.

Authors

Yulian Zhou, Yanshu Wang, Max Tischfield, John Williams, Philip M. Smallwood, Amir Rattner, Makoto M. Taketo, Jeremy Nathans

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Figure 8

Production of stabilized β-catenin in ECs rescues NdpKO retinal vascular defects.

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Production of stabilized β-catenin in ECs rescues NdpKO retinal vascular...
(A) Retinal vasculature at P16 in WT, NdpKO, and NdpKO Ctnnb1flex3/+ Pdgfb-CreER mice treated with 20 μg 4HT at P2. Cross sections (upper) and flat mounts (lower; vascular depth color-coded). GCL, ganglion cell layer; ONL, outer nuclear layer. Scale bars: 200 μm. (B) Vascular density at P16 and P40. Box and whisker plot parameters; see Methods. (C) BRB integrity assessed by sulfo-NHS-biotin leakage in adult WT, NdpKO, and NdpKO Ctnnb1flex3/+ Pdgfb-CreER retinas. NdpKO Ctnnb1flex3/+ Pdgfb-CreER mice were treated with 20 μg 4HT at P3. Scale bar: 1 mm. (D) Retinas from NdpKO Ctnnb1flex3/+ Pdgfb-CreER mice treated with 20 μg 4HT at P2–P3. White arrows, boundary between PLVAP+Claudin5– and PLVAP–Claudin5+ territories. Scale bars: 200 μm. (E) Flat-mount retinas from NdpKO Ctnnb1flex3/+ Pdgfb-CreER mice treated with 1 μg 4HT at P2. Depth is color coded. Scale bar: 200 μm. (F) Whole P10 retina RNAseq from WT, NdpKO, Ctnnb1flex3/+ Pdgfb-CreER, and NdpKO Ctnnb1flex3/+ Pdgfb-CreER mice treated with 20 μg 4HT at P3. Upper panel, ratios of transcript abundances: NdpKO Ctnnb1flex3/+ Pdgfb-CreER versus NdpKO (y axis) and WT versus NdpKO (x axis). Least squares regression line (blue; R2 = 0.62) and orthogonal (Deming) regression (red; ref. 69). Lower panel, ratios of transcript abundances: Ctnnb1flex3/+ Pdgfb-CreER versus WT (y axis) and WT versus NdpKO (x axis). (The upper left point is likely an artifact and was not included in the line fitting, and the upper right point was also omitted from the line fitting so that it would not dominate the regression calculation). (G) Peripheral retinas of WT and Ctnnb1flex3/+ Pdgfb-CreER mice treated with 50 to 100 μg 4HT at P2–P4. Scale bars: 200 μm. (H) Left panel, horizontal eye position during OKR representative recordings. Right panel, OKR quantification. n = 3 or more mice per genotype.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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