title: Neuralized promotes basal to apical transcytosis of delta in epithelial cells.
abstract: Notch receptors mediate short-range signaling controlling many developmental decisions in metazoans. Activation of Notch requires the ubiquitin-dependent endocytosis of its ligand Delta. How ligand endocytosis in signal-sending cells regulates receptor activation in juxtaposed signal-receiving cells remains largely unknown. We show here that a pool of Delta localizes at the basolateral membrane of signal-sending sensory organ precursor cells in the dorsal thorax neuroepithelium of Drosophila and that Delta is endocytosed in a Neuralized-dependent manner from this basolateral membrane. This basolateral pool of Delta is segregated from Notch that accumulates apically. Using a compartimentalized antibody uptake assay, we show that murine Delta-like 1 is similarly internalized by mNeuralized2 from the basolateral membrane of polarized Madin-Darby canine kidney cells and that internalized ligands are transcytosed to the apical plasma membrane where mNotch1 accumulates. Thus, endocytosis of Delta by Neuralized relocalizes Delta from the basolateral to the apical membrane domain. We speculate that this Neuralized-dependent transcytosis regulates the signaling activity of Delta by relocalizing Delta from a membrane domain where it cannot interact with Notch to another membrane domain where it can bind and activate Notch.
authors.affiliation: Centre National de la Recherche Scientifique Unité Mixte de Recherche 6061, Institut de Génétique et Développement de Rennes, Université de Rennes 1, 35000 Rennes, France.
authors.forename: Najate
authors.initials: N
authors.lastname: Benhra
authors.forename: Françoise
authors.initials: F
authors.lastname: Vignaux
authors.forename: Aurore
authors.initials: A
authors.lastname: Dussert
authors.forename: François
authors.initials: F
authors.lastname: Schweisguth
authors.forename: Roland
authors.initials: R
authors.lastname: Le Borgne
mesh_terms: D000818:Animals; D016764:Cell Polarity; D004285:Dogs; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism; D004705:Endocytosis; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011679:Pupa / Q000166:cytology / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D012679:Sense Organs / Q000166:cytology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C064045:delta protein; D044767:Ubiquitin-Protein Ligases; C071006:neur protein, Drosophila
references.citation: J Biol Chem. 2006 Nov 24;281(47):36391-400
references.pmid: 17003037
references.citation: Development. 2005 Apr;132(8):1751-62
references.pmid: 15790962
references.citation: Development. 2005 Jun;132(12):2883-94
references.pmid: 15930117
references.citation: Oncogene. 2008 Sep 1;27(38):5148-67
references.pmid: 18758484
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5637-42
references.pmid: 11344304
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11212-7
references.pmid: 18676613
references.citation: Dev Cell. 2003 Aug;5(2):231-43
references.pmid: 12919675
references.citation: J Biol Chem. 2008 Feb 15;283(7):3846-53
references.pmid: 18077452
references.citation: Mol Biol Cell. 2007 Jan;18(1):1-13
references.pmid: 17065551
references.citation: Curr Opin Cell Biol. 2008 Aug;20(4):462-9
references.pmid: 18511252
references.citation: Mech Dev. 1997 Apr;63(1):61-74
references.pmid: 9178257
references.citation: Dev Cell. 2005 Sep;9(3):351-63
references.pmid: 16137928
references.citation: Curr Biol. 2003 May 13;13(10):854-60
references.pmid: 12747835
references.citation: Genes Cells. 2007 Jan;12(1):89-103
references.pmid: 17212657
references.citation: Curr Biol. 2004 Feb 3;14(3):R129-38
references.pmid: 14986688
references.citation: Dev Biol. 2001 Mar 1;231(1):217-33
references.pmid: 11180964
references.citation: Dev Cell. 2007 Dec;13(6):783-95
references.pmid: 18061562
references.citation: J Cell Biol. 1994 Apr;125(1):67-86
references.pmid: 8138576
references.citation: J Cell Sci. 1999 Oct;112 ( Pt 19):3289-97
references.pmid: 10504334
references.citation: Dev Biol. 1997 Dec 15;192(2):585-98
references.pmid: 9441691
references.citation: Sci STKE. 2007 Apr 10;2007(381):re3
references.pmid: 17426346
references.citation: Development. 2005 Sep;132(18):4041-50
references.pmid: 16093323
references.citation: Development. 2004 Nov;131(21):5355-66
references.pmid: 15469967
references.citation: Nat Struct Mol Biol. 2007 Apr;14(4):295-300
references.pmid: 17401372
references.citation: Development. 1989 Oct;107(2):389-405
references.pmid: 2517255
references.citation: Cell. 2005 Sep 9;122(5):763-73
references.pmid: 16137758
references.citation: Cell. 2009 Apr 17;137(2):216-33
references.pmid: 19379690
references.citation: Dev Cell. 2001 Dec;1(6):807-16
references.pmid: 11740942
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7638-43
references.pmid: 12794186
references.citation: Nat Cell Biol. 2009 Jul;11(7):815-24
references.pmid: 19543274
references.citation: Dev Cell. 2006 Feb;10(2):245-55
references.pmid: 16459303
references.citation: Dev Cell. 2006 Feb;10(2):257-64
references.pmid: 16459304
references.citation: Dev Cell. 2003 Jul;5(1):139-48
references.pmid: 12852858
references.citation: Dev Biol. 1990 Nov;142(1):13-30
references.pmid: 2227090
references.citation: J Cell Biol. 2007 Feb 12;176(4):445-58
references.pmid: 17296795
references.citation: Development. 2004 Mar;131(5):965-73
references.pmid: 14973298
references.citation: Development. 2004 Nov;131(21):5367-80
references.pmid: 15469974
references.citation: Genetics. 2009 Aug;182(4):1101-8
references.pmid: 19528324
references.citation: Dev Cell. 2001 Dec;1(6):795-806
references.pmid: 11740941
references.citation: Annu Rev Cell Dev Biol. 2006;22:181-206
references.pmid: 16776558