title: Molecular heterogeneity in the choroid plexus epithelium: the 22-member γ-protocadherin family is differentially expressed, apically localized, and implicated in CSF regulation.
abstract: The choroid plexus (CP) epithelium develops from the ependyma that lines the ventricular system, and plays a critical role in the development and function of the brain. In addition to being the primary site of CSF production, the CP maintains the blood-CSF barrier via apical tight junctions between epithelial cells. Here we show that the 22-member γ-protocadherin (γ-Pcdh) family of cell adhesion molecules, which we have implicated previously in synaptogenesis and neuronal survival, is highly expressed by both CP epithelial and ependymal cells, in which γ-Pcdh protein localization is, surprisingly, tightly restricted to the apical membrane. Multi-label immunostaining demonstrates that γ-Pcdhs are excluded from tight junctions, basolateral adherens junctions, and apical cilia tufts. RT-PCR analysis indicates that, as a whole, the CP expresses most members of the Pcdh-γ gene family. Immunostaining using novel monoclonal antibodies specific for single γ-Pcdh proteins shows that individual epithelial cells differ in their apically localized γ-Pcdh repertoire. Restricted mutation of the Pcdh-γ locus in the choroid plexus and ependyma leads to significant reductions in ventricular volume, without obvious disruptions of epithelial apical-basal polarity. Together, these results suggest an unsuspected role for the γ-Pcdhs in CSF production and demonstrate a surprising molecular heterogeneity in the CP epithelium.
authors.affiliation: Department of Biology, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lobas
authors.forename: Lindsey
authors.initials: L
authors.lastname: Helsper
authors.forename: Claire G
authors.initials: CG
authors.lastname: Vernon
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schreiner
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Thedens
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Weiner
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D002552:Cerebral Ventricles / Q000378:metabolism / Q000648:ultrastructure; D002555:Cerebrospinal Fluid / Q000502:physiology; D002831:Choroid Plexus / Q000033:anatomy & histology*; D004622:Embryo, Mammalian; D004805:Ependyma / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D004848:Epithelium / Q000033:anatomy & histology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; C481963:FOXJ1 protein, mouse; D051858:Forkhead Transcription Factors; C464785:Gamma-protocadherins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D014404:Tubulin; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
references.citation: Nat Genet. 2005 Feb;37(2):171-6
references.pmid: 15640798
references.citation: Curr Opin Cell Biol. 2007 Oct;19(5):584-92
references.pmid: 17936607
references.citation: Cell. 1999 Jun 11;97(6):779-90
references.pmid: 10380929
references.citation: J Cell Sci. 1995 Dec;108 ( Pt 12):3765-73
references.pmid: 8719883
references.citation: Nat Rev Neurosci. 2007 Jan;8(1):11-20
references.pmid: 17133224
references.citation: J Neurosci. 2003 Jun 15;23(12):5096-104
references.pmid: 12832533
references.citation: Microsc Res Tech. 2001 Jan 1;52(1):112-29
references.pmid: 11135454
references.citation: J Biol Chem. 2010 Apr 23;285(17):13193-200
references.pmid: 20159971
references.citation: Genesis. 2000 Nov-Dec;28(3-4):147-55
references.pmid: 11105057
references.citation: Neuron. 2002 Dec 5;36(5):843-54
references.pmid: 12467588
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14893-8
references.pmid: 20679223
references.citation: Am J Pathol. 1996 Jun;148(6):1819-38
references.pmid: 8669469
references.citation: Brain Res Mol Brain Res. 2002 Jan 31;98(1-2):119-23
references.pmid: 11834302
references.citation: Am J Physiol Renal Physiol. 2002 Sep;283(3):F454-63
references.pmid: 12167596
references.citation: J Biol Chem. 2004 Nov 19;279(47):49508-16
references.pmid: 15347688
references.citation: Microsc Res Tech. 2001 Jan 1;52(1):49-59
references.pmid: 11135448
references.citation: Nature. 2007 Sep 6;449(7158):87-91
references.pmid: 17805295
references.citation: Nat Neurosci. 2010 Jun;13(6):700-7
references.pmid: 20473291
references.citation: Acta Neuropathol. 2010 Jan;119(1):75-88
references.pmid: 20033190
references.citation: Am J Respir Cell Mol Biol. 2007 May;36(5):515-9
references.pmid: 17255554
references.citation: Cell Tissue Res. 1999 May;296(2):259-69
references.pmid: 10382270
references.citation: Nat Immunol. 2009 May;10(5):514-23
references.pmid: 19305396
references.citation: Mol Cell Neurosci. 2005 Aug;29(4):603-16
references.pmid: 15964765
references.citation: J Cell Biol. 2005 Nov 7;171(3):549-58
references.pmid: 16260500
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):482-8
references.pmid: 16099635
references.citation: J Neurosci. 2009 Sep 23;29(38):11723-31
references.pmid: 19776259
references.citation: Curr Opin Neurobiol. 2005 Feb;15(1):73-80
references.pmid: 15721747
references.citation: Nature. 2010 Jul 29;466(7306):632-6
references.pmid: 20639864
references.citation: Results Probl Cell Differ. 2006;43:259-80
references.pmid: 17068976
references.citation: PLoS Genet. 2009 Nov;5(11):e1000745
references.pmid: 19956686
references.citation: Semin Immunopathol. 2009 Nov;31(4):497-511
references.pmid: 19779720
references.citation: Pflugers Arch. 2007 Apr;454(1):1-18
references.pmid: 17120021
references.citation: Mol Cell Biochem. 2007 Jul;301(1-2):235-9
references.pmid: 17318408
references.citation: Cell. 2010 Oct 29;143(3):343-53
references.pmid: 21029858
references.citation: Development. 2008 Dec;135(24):4153-64
references.pmid: 19029045
references.citation: Nat Rev Neurosci. 2009 Feb;10(2):153-63
references.pmid: 19153578
references.citation: Genetics. 2005 Apr;169(4):2179-88
references.pmid: 15744052
references.citation: J Anat. 1979 Dec;129(Pt 4):777-93
references.pmid: 536314
references.citation: Genes Dev. 2002 Aug 1;16(15):1890-905
references.pmid: 12154121
references.citation: Dev Genes Evol. 2007 May;217(5):337-51
references.pmid: 17429686
references.citation: Neuroscience. 2007 Jan 19;144(2):579-603
references.pmid: 17110050
references.citation: Neuron. 1998 Jun;20(6):1137-51
references.pmid: 9655502
references.citation: J Neurocytol. 2001 May;30(5):365-77
references.pmid: 11951048
references.citation: J Biol Chem. 2006 Oct 13;281(41):30551-60
references.pmid: 16893882
references.citation: J Cell Sci. 2006 Mar 15;119(Pt 6):1184-95
references.pmid: 16507588
references.citation: Physiol Rev. 1971 Apr;51(2):273-311
references.pmid: 4930496
references.citation: Neuroscience. 2004;129(4):957-70
references.pmid: 15561411
references.citation: Am J Physiol. 1963 Sep;205:617-24
references.pmid: 14065919
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):8-14
references.pmid: 15574493
references.citation: Genome Res. 2001 Mar;11(3):389-404
references.pmid: 11230163
references.citation: Genes Dev. 2006 Dec 1;20(23):3199-214
references.pmid: 17158740
references.citation: Mol Cell. 2002 Jul;10(1):21-33
references.pmid: 12150904
references.citation: Mol Cell Proteomics. 2010 Jan;9(1):71-83
references.pmid: 19843561
references.citation: J Neurosci. 2010 Feb 17;30(7):2600-10
references.pmid: 20164345
references.citation: Cerebrospinal Fluid Res. 2005 Sep 30;2:8
references.pmid: 16197544
references.citation: J Biol Chem. 2006 Aug 4;281(31):21735-21744
references.pmid: 16751190