title: Canonical WNT signaling components in vascular development and barrier formation.
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.forename: Yulian
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Wang
authors.forename: Max
authors.initials: M
authors.lastname: Tischfield
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.forename: Philip M
authors.initials: PM
authors.lastname: Smallwood
authors.forename: Amir
authors.initials: A
authors.lastname: Rattner
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001813:Blood-Retinal Barrier / Q000502:physiology*; D005136:Eye Proteins / Q000235:genetics; D051157:Frizzled Receptors / Q000502:physiology; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000502:physiology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000502:physiology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D012160:Retina / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: C495267:CTNNB1 protein, mouse; D005136:Eye Proteins; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D051176:beta Catenin; D013629:Tamoxifen; C016601:afimoxifene
references.citation: Br J Ophthalmol. 2011 Apr;95(4):574-9
references.pmid: 21097938
references.citation: J Neurosci. 2002 Jun 1;22(11):4286-92
references.pmid: 12040033
references.citation: Hum Mol Genet. 2008 Jun 1;17(11):1605-12
references.pmid: 18263894
references.citation: Adv Drug Deliv Rev. 2014 Jun;72:94-109
references.pmid: 24462453
references.citation: Development. 2011 Mar;138(6):1161-72
references.pmid: 21343368
references.citation: Ophthalmic Genet. 2007 Dec;28(4):220-3
references.pmid: 18161623
references.citation: Genesis. 2008 Feb;46(2):74-80
references.pmid: 18257043
references.citation: Elife. 2013 Dec 17;2:e01482
references.pmid: 24347548
references.citation: Ann Intern Med. 1981 Apr;94(4 pt 1):449-54
references.pmid: 6782926
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9856-61
references.pmid: 23716654
references.citation: Pharmacol Rev. 2005 Jun;57(2):173-85
references.pmid: 15914466
references.citation: J Cell Biol. 2008 Nov 3;183(3):409-17
references.pmid: 18955553
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3299-304
references.pmid: 12626757
references.citation: Science. 2012 Jul 6;337(6090):59-64
references.pmid: 22653731
references.citation: Cell. 2011 Sep 16;146(6):873-87
references.pmid: 21925313
references.citation: Gene Expr Patterns. 2011 Jan-Feb;11(1-2):151-5
references.pmid: 21055480
references.citation: Circ Res. 2007 Feb 2;100(2):158-73
references.pmid: 17272818
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13203-7
references.pmid: 10557298
references.citation: Circ Res. 2012 Jan 6;110(1):47-58
references.pmid: 22076635
references.citation: Biol Chem. 1999 Dec;380(12):1435-8
references.pmid: 10661871
references.citation: PLoS One. 2010 Oct 29;5(10):e13741
references.pmid: 21060791
references.citation: Ophthalmologica. 2012;227 Suppl 1:2-10
references.pmid: 22517120
references.citation: Neuron. 2014 Jan 8;81(1):103-19
references.pmid: 24411735
references.citation: PLoS One. 2012;7(1):e30203
references.pmid: 22272305
references.citation: Acta Neuropathol. 2010 Dec;120(6):689-705
references.pmid: 20830478
references.citation: Nat Commun. 2013;4:2609
references.pmid: 24153254
references.citation: Genes Dev. 2011 Dec 15;25(24):2631-43
references.pmid: 22190459
references.citation: Cell. 2009 Oct 16;139(2):285-98
references.pmid: 19837032
references.citation: Development. 2011 May;138(10):1877-92
references.pmid: 21521735
references.citation: PLoS One. 2008 Apr 30;3(4):e2055
references.pmid: 18446207
references.citation: Cell. 2012 Dec 7;151(6):1332-44
references.pmid: 23217714
references.citation: Invest Ophthalmol Vis Sci. 2012 May 14;53(6):2873-9
references.pmid: 22427576
references.citation: Kidney Int. 2005 May;67(5):1668-71
references.pmid: 15840009
references.citation: J Cell Sci. 2013 May 1;126(Pt 9):2060-8
references.pmid: 23444378
references.citation: Cell Calcium. 2005 Sep-Oct;38(3-4):439-46
references.pmid: 16099039
references.citation: Dev Biol. 2001 Feb 15;230(2):230-42
references.pmid: 11161575
references.citation: Cell. 2009 Oct 16;139(2):299-311
references.pmid: 19837033
references.citation: Nature. 2000 Sep 28;407(6803):535-8
references.pmid: 11029008
references.citation: Science. 2008 Nov 21;322(5905):1247-50
references.pmid: 19023080
references.citation: Dev Biol. 2011 Nov 15;359(2):222-9
references.pmid: 21924256
references.citation: Am J Hum Genet. 2010 Feb 12;86(2):240-7
references.pmid: 20159111
references.citation: Trends Mol Med. 2010 Sep;16(9):417-25
references.pmid: 20688566
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):641-6
references.pmid: 19129494
references.citation: J Anat. 1979 Dec;129(Pt 4):777-93
references.pmid: 536314
references.citation: Cell. 2001 Nov 16;107(4):513-23
references.pmid: 11719191
references.citation: Cell. 2004 Mar 19;116(6):883-95
references.pmid: 15035989
references.citation: Elife. 2013 Mar 19;2:e00638
references.pmid: 23538852
references.citation: Cold Spring Harb Perspect Biol. 2013 Mar 01;5(3):a015081
references.pmid: 23085770
references.citation: Nucleic Acids Res. 2010 Sep;38(17):5735-45
references.pmid: 20460455
references.citation: J Cell Biol. 2002 Apr 15;157(2):303-14
references.pmid: 11956231
references.citation: Ophthalmology. 2011 Oct;118(10):2070-5
references.pmid: 21868098
references.citation: Circ Res. 2007 Feb 2;100(2):174-90
references.pmid: 17272819
references.citation: J Neurosci. 2001 Jul 1;21(13):4761-71
references.pmid: 11425903
references.citation: Hum Mutat. 2010 Jun;31(6):656-66
references.pmid: 20340138
references.citation: EMBO J. 2012 Jun 13;31(12):2714-36
references.pmid: 22617422
references.citation: J Neurosci. 2009 Jul 8;29(27):8621-9
references.pmid: 19587267
references.citation: EMBO J. 1999 Nov 1;18(21):5931-42
references.pmid: 10545105
references.citation: Genes Dev. 2013 Nov 1;27(21):2305-19
references.pmid: 24186977
references.citation: Genes Dev. 2011 Sep 1;25(17):1783-95
references.pmid: 21856776
references.citation: EMBO J. 2014 Jan 13;33(2):146-56
references.pmid: 24413017
references.citation: Nat Med. 2013 Dec;19(12):1584-96
references.pmid: 24309662
references.citation: Hum Mutat. 2005 Aug;26(2):104-12
references.pmid: 15981244
references.citation: Semin Cell Dev Biol. 1998 Jun;9(3):285-92
references.pmid: 9665864
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4914-9
references.pmid: 21383188
references.citation: Invest Ophthalmol Vis Sci. 2011 Aug 16;52(9):6452-61
references.pmid: 21743011
references.citation: Development. 2012 Jun;139(12):2118-29
references.pmid: 22573616
references.citation: J Cell Biol. 2003 Sep 15;162(6):1111-22
references.pmid: 12975353