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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

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 1

Effects of eliminating Ctnnb1 or Lrp5 and Lrp6 in ECs on vascularization of the E11.5 CNS.

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Effects of eliminating Ctnnb1 or Lrp5 and Lrp6 in ECs on vascularization...
(A) Bleeding in the hindbrain, midbrain, and forebrain of a Lrp5–/– Lrp6CKO/CKO Tie2-Cre embryo at E11.5 (arrowheads, right panel). Many embryos of this genotype also show bleeding in the spinal cord. Left, control embryo. (B) Transverse Z-stacked projections at E11.5 show severe vascularization defects in the Lrp5–/– Lrp6CKO/CKO Tie2-Cre and Ctnnb1CKO/CKO Tie2-Cre hindbrain and an intermediate vascularization defect in the Ctnnb1CKO/dm Tie2-Cre hindbrain (compare the regions highlighted by the arrows). Anti-ICAM2 stains ECs more strongly outside the CNS. GS lectin binds ECs and macrophages, which invade the hypovascularized CNS. Scale bar: 200 μm. (C) Spinal cord and hindbrain vascularization defects in E11.5 embryo whole mounts imaged from the dorsal surface. Z-stacks of approximately 70-μm thickness are shown. Smooth muscle actin highlights the somites. Lrp5–/– Lrp6CKO/CKO Tie2-Cre and Ctnnb1CKO/CKO Tie2-Cre embryos (center) show severe hypovascularization, formation of glomeruloid bodies, and bleeding within the spinal cord (white). The Ctnnb1CKO/dm Tie2-Cre embryo (far right) shows an intermediate vascularization defect. Anterior (A) is at the top; posterior (P) is at the bottom. (D) Optical sections in the sagittal plane of E11.5 embryos. The top 3 panels (Lrp5+/+ Lrp6CKO/CKO Tie2-Cre, Lrp5+/– Lrp6CKO/CKO Tie2-Cre, and Lrp5–/– Lrp6CKO/+ Tie2-Cre) show normal or nearly normal CNS vascularization. The left and middle bottom panels (Lrp5–/– Lrp6CKO/CKO Tie2-Cre and Ctnnb1CKO/CKO Tie2-Cre) show severe defects in CNS vascularization with bleeding that is most severe in the cervical spinal cord (arrowheads). The rightmost bottom panel (Ctnnb1CKO/dm Tie2-Cre) shows an intermediate vascularization defect in the spinal cord (arrowhead). Scale bar: 500 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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