title: LGN regulates mitotic spindle orientation during epithelial morphogenesis.
abstract: Coordinated cell polarization and mitotic spindle orientation are thought to be important for epithelial morphogenesis. Whether spindle orientation is indeed linked to epithelial morphogenesis and how it is controlled at the molecular level is still unknown. Here, we show that the NuMA- and Galpha-binding protein LGN is required for directing spindle orientation during cystogenesis of MDCK cells. LGN localizes to the lateral cell cortex, and is excluded from the apical cell cortex of dividing cells. Depleting LGN, preventing its cortical localization, or disrupting its interaction with endogenous NuMA or Galpha proteins all lead to spindle misorientation and abnormal cystogenesis. Moreover, artificial mistargeting of endogenous LGN to the apical membrane results in a near 90 degrees rotation of the spindle axis and profound cystogenesis defects that are dependent on cell division. The normal apical exclusion of LGN during mitosis appears to be mediated by atypical PKC. Thus, cell polarization-mediated spatial restriction of spindle orientation determinants is critical for epithelial morphogenesis.
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zheng
authors.forename: Huabin
authors.initials: H
authors.lastname: Zhu
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Wan
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Zhuoni
authors.initials: Z
authors.lastname: Xiao
authors.forename: David P
authors.initials: DP
authors.lastname: Siderovski
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Du
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D016764:Cell Polarity; D049109:Cell Proliferation; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D004848:Epithelium / Q000196:embryology*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009024:Morphogenesis / Q000502:physiology*; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D034521:Nuclear Matrix-Associated Proteins; C115015:PKC-3 protein; D011493:Protein Kinase C
references.citation: Biochim Biophys Acta. 2005 Sep 10;1745(2):254-64
references.pmid: 15946753
references.citation: Science. 2003 Jun 20;300(5627):1957-61
references.pmid: 12750478
references.citation: Nat Cell Biol. 2009 Apr;11(4):365-74
references.pmid: 19337318
references.citation: J Cell Biol. 2007 Oct 8;179(1):15-22
references.pmid: 17908918
references.citation: Mol Biol Cell. 2003 Feb;14(2):748-63
references.pmid: 12589067
references.citation: Nat Cell Biol. 2008 Jan;10(1):93-101
references.pmid: 18084280
references.citation: Nat Neurosci. 2007 Nov;10(11):1440-8
references.pmid: 17934458
references.citation: Curr Opin Cell Biol. 2003 Feb;15(1):73-81
references.pmid: 12517707
references.citation: Curr Biol. 2002 Nov 19;12(22):1928-33
references.pmid: 12445386
references.citation: Curr Biol. 2005 Sep 20;15(18):1640-4
references.pmid: 16169485
references.citation: Dev Cell. 2006 Jun;10(6):731-42
references.pmid: 16740476
references.citation: J Cell Sci. 2004 Dec 15;117(Pt 26):6391-400
references.pmid: 15561764
references.citation: Dev Cell. 2005 Apr;8(4):461-5
references.pmid: 15809029
references.citation: Science. 1999 Oct 29;286(5441):971-4
references.pmid: 10542155
references.citation: Curr Opin Cell Biol. 2006 Dec;18(6):648-57
references.pmid: 17046223
references.citation: J Cell Biol. 2008 Nov 17;183(4):625-33
references.pmid: 19001128
references.citation: Cell. 1996 Nov 1;87(3):447-58
references.pmid: 8898198
references.citation: Nat Rev Mol Cell Biol. 2008 Nov;9(11):887-901
references.pmid: 18946477
references.citation: J Cell Biol. 1997 Sep 8;138(5):1055-66
references.pmid: 9281583
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16584-9
references.pmid: 16275912
references.citation: Int Rev Cytol. 1971;31:169-213
references.pmid: 4400359
references.citation: Nat Rev Mol Cell Biol. 2002 Jul;3(7):531-7
references.pmid: 12094219
references.citation: Cell. 2007 Jan 26;128(2):383-97
references.pmid: 17254974
references.citation: J Cell Biol. 2002 Apr 1;157(1):161-72
references.pmid: 11927608
references.citation: Methods. 2003 Jul;30(3):256-68
references.pmid: 12798140
references.citation: Mol Biol Cell. 2003 Aug;14(8):3144-55
references.pmid: 12925752
references.citation: Nat Cell Biol. 2001 Dec;3(12):1069-75
references.pmid: 11781568
references.citation: Annu Rev Biochem. 2004;73:925-51
references.pmid: 15189163
references.citation: J Biol Chem. 2001 Jan 12;276(2):1585-93
references.pmid: 11042168
references.citation: Cell. 2009 Sep 18;138(6):1150-63
references.pmid: 19766567
references.citation: J Biol Chem. 2005 Feb 25;280(8):6761-5
references.pmid: 15632202
references.citation: Mol Cell Biol. 2009 May;29(10):2816-27
references.pmid: 19273597
references.citation: Dev Cell. 2007 Dec;13(6):796-811
references.pmid: 18061563
references.citation: Science. 2003 Jul 25;301(5632):518-21
references.pmid: 12881570
references.citation: Semin Cell Dev Biol. 2009 Oct;20(8):972-7
references.pmid: 19447051
references.citation: Nat Cell Biol. 2006 Jun;8(6):586-93
references.pmid: 16648846
references.citation: Cell. 2004 Nov 12;119(4):503-16
references.pmid: 15537540
references.citation: J Cell Sci. 2009 May 15;122(Pt 10):1595-606
references.pmid: 19401335
references.citation: Cell. 2005 Jul 15;122(1):119-31
references.pmid: 16009138
references.citation: Nature. 2007 May 24;447(7143):493-6
references.pmid: 17495931
references.citation: Development. 2006 Feb;133(3):529-36
references.pmid: 16396904
references.citation: Nat Rev Cancer. 2005 Sep;5(9):675-88
references.pmid: 16148884
references.citation: Nat Cell Biol. 2005 Dec;7(12):1179-90
references.pmid: 16299499
references.citation: J Cell Biol. 2001 Feb 5;152(3):425-34
references.pmid: 11157972
references.citation: Curr Biol. 2004 Aug 24;14(16):R674-85
references.pmid: 15324689
references.citation: EMBO J. 2007 Mar 21;26(6):1487-98
references.pmid: 17318179
references.citation: Curr Opin Cell Biol. 2004 Apr;16(2):195-205
references.pmid: 15196564
references.citation: J Cell Sci. 2003 Jul 15;116(Pt 14):2895-906
references.pmid: 12771187
references.citation: Nat Genet. 2008 Aug;40(8):1010-5
references.pmid: 18604206
references.citation: Cell. 2005 Dec 29;123(7):1323-35
references.pmid: 16377571
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14306-11
references.pmid: 17726110
references.citation: Dev Biol. 2008 Mar 1;315(1):42-54
references.pmid: 18234174
references.citation: Mol Biol Cell. 2009 Aug;20(16):3740-50
references.pmid: 19553471
references.citation: Nat Cell Biol. 2006 Jun;8(6):594-600
references.pmid: 16648843
references.citation: J Biol Chem. 2008 Dec 26;283(52):36698-710
references.pmid: 18984596