title: LIS1 controls mitosis and mitotic spindle organization via the LIS1-NDEL1-dynein complex.
abstract: Heterozygous LIS1 mutations are responsible for the human neuronal migration disorder lissencephaly. Mitotic functions of LIS1 have been suggested from many organisms throughout evolution. However, the cellular functions of LIS1 at distinct intracellular compartments such as the centrosome and the cell cortex have not been well defined especially during mitotic cell division. Here, we used detailed cellular approaches and time-lapse live cell imaging of mitosis from Lis1 mutant mouse embryonic fibroblasts to reveal critical roles of LIS1 in mitotic spindle regulation. We found that LIS1 is required for the tight control of chromosome congression and segregation to dictate kinetochore-microtubule (MT) interactions and anaphase progression. In addition, LIS1 is essential for the establishment of mitotic spindle pole integrity by maintaining normal centrosome number. Moreover, LIS1 plays crucial roles in mitotic spindle orientation by increasing the density of astral MT plus-end movements toward the cell cortex, which enhances cortical targeting of LIS1-dynein complex. Overexpression of NDEL1-dynein and MT stabilization rescues spindle orientation defects in Lis1 mutants, demonstrating that mouse LIS1 acts via the LIS1-NDEL1-dynein complex to regulate astral MT plus-ends dynamics and establish proper contacts of MTs with the cell cortex to ensure precise cell division.
authors.affiliation: Department of Pediatrics, Institute for Human Genetics.
authors.forename: Hyang Mi
authors.initials: HM
authors.lastname: Moon
authors.forename: Yong Ha
authors.initials: YH
authors.lastname: Youn
authors.forename: Hayley
authors.initials: H
authors.lastname: Pemble
authors.forename: Jessica
authors.initials: J
authors.lastname: Yingling
authors.forename: Torsten
authors.initials: T
authors.lastname: Wittmann
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D018385:Centrosome; D002540:Cerebral Cortex; D020090:Chromosome Segregation; D004398:Dyneins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D054082:Lissencephaly / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D055550:Protein Stability; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; C486015:Ndel1 protein, mouse; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D004398:Dyneins
references.citation: Cell. 1996 Nov 1;87(3):447-58
references.pmid: 8898198
references.citation: J Cell Biol. 2004 Feb 16;164(4):557-66
references.pmid: 14970193
references.citation: Mol Oncol. 2011 Aug;5(4):324-35
references.pmid: 21646054
references.citation: Semin Cell Dev Biol. 2010 May;21(3):283-9
references.pmid: 20109571
references.citation: J Cell Biol. 2007 Oct 22;179(2):321-30
references.pmid: 17954613
references.citation: Nature. 1986 Dec 18-31;324(6098):621
references.pmid: 3796729
references.citation: Cell. 2012 Feb 3;148(3):502-14
references.pmid: 22304918
references.citation: Nat Cell Biol. 2000 Nov;2(11):784-91
references.pmid: 11056532
references.citation: Trends Cell Biol. 2002 Jul;12(7):332-9
references.pmid: 12185850
references.citation: J Cell Sci. 2000 Sep;113 ( Pt 17):3013-23
references.pmid: 10934040
references.citation: J Neurosci. 2003 Mar 1;23(5):1719-29
references.pmid: 12629176
references.citation: Mol Cell Biol. 2006 Dec;26(23):9016-34
references.pmid: 17015463
references.citation: Neuron. 2000 Dec;28(3):665-79
references.pmid: 11163258
references.citation: Nat Genet. 1998 Aug;19(4):333-9
references.pmid: 9697693
references.citation: J Cell Biol. 2009 Mar 23;184(6):895-908
references.pmid: 19289791
references.citation: Curr Opin Cell Biol. 2002 Feb;14(1):25-34
references.pmid: 11792541
references.citation: Structure. 2007 Nov;15(11):1467-81
references.pmid: 17997972
references.citation: J Cell Biol. 2009 Jun 1;185(5):859-74
references.pmid: 19468067
references.citation: J Cell Biol. 2011 Feb 7;192(3):433-45
references.pmid: 21282465
references.citation: Mol Biol Cell. 1995 Mar;6(3):297-310
references.pmid: 7612965
references.citation: Nature. 2009 Jul 9;460(7252):278-82
references.pmid: 19506557
references.citation: Neuron. 2000 Dec;28(3):697-711
references.pmid: 11163260
references.citation: J Cell Biol. 2005 Sep 12;170(6):935-45
references.pmid: 16144905
references.citation: Mol Biol Cell. 2001 Jun;12(6):1687-97
references.pmid: 11408577
references.citation: Nature. 1993 Aug 19;364(6439):717-21
references.pmid: 8355785
references.citation: Mol Biol Cell. 2003 Aug;14(8):3144-55
references.pmid: 12925752
references.citation: Curr Biol. 2012 Apr 10;22(7):632-7
references.pmid: 22445300
references.citation: Mol Cell Biol. 2005 Sep;25(17):7812-27
references.pmid: 16107726
references.citation: Nat Rev Cancer. 2002 Nov;2(11):815-25
references.pmid: 12415252
references.citation: Traffic. 2000 Dec;1(12):927-34
references.pmid: 11208082
references.citation: Nat Cell Biol. 2009 Aug;11(8):994-1001
references.pmid: 19620968
references.citation: Curr Opin Cell Biol. 2002 Feb;14(1):44-9
references.pmid: 11792543
references.citation: Oncogene. 2010 Nov 11;29(45):6040-50
references.pmid: 20697357
references.citation: Curr Biol. 1998 Mar 26;8(7):377-85
references.pmid: 9545195
references.citation: Cytoskeleton (Hoboken). 2011 Mar;68(3):157-74
references.pmid: 21294277
references.citation: Mol Biol Cell. 2000 May;11(5):1765-74
references.pmid: 10793150
references.citation: Dev Biol. 2002 Apr 15;244(2):305-18
references.pmid: 11944939
references.citation: Genes Dev. 2008 Aug 15;22(16):2189-203
references.pmid: 18662975
references.citation: J Cell Biol. 2000 Aug 7;150(3):681-8
references.pmid: 10931877
references.citation: J Cell Biol. 2007 Aug 13;178(4):583-94
references.pmid: 17682047
references.citation: Cell. 2008 Feb 8;132(3):474-86
references.pmid: 18267077
references.citation: J Cell Biol. 2011 Aug 22;194(4):631-42
references.pmid: 21844209
references.citation: Nat Neurosci. 2006 Jan;9(1):50-7
references.pmid: 16369480
references.citation: Curr Biol. 1998 Apr 23;8(9):541-4
references.pmid: 9560347
references.citation: Nat Rev Mol Cell Biol. 2009 Jul;10(7):478-87
references.pmid: 19546858
references.citation: Curr Biol. 2009 Feb 10;19(3):196-205
references.pmid: 19185494
references.citation: Mol Cell Biol. 2002 May;22(9):3089-102
references.pmid: 11940666
references.citation: Cell. 2010 Apr 16;141(2):304-14
references.pmid: 20403325
references.citation: J Neurosci. 2010 Feb 24;30(8):3002-12
references.pmid: 20181597
references.citation: J Cell Biol. 2002 Mar 18;156(6):959-68
references.pmid: 11889140
references.citation: Nat Rev Mol Cell Biol. 2009 Jan;10(1):9-20
references.pmid: 19197328
references.citation: Annu Rev Cell Dev Biol. 2004;20:759-79
references.pmid: 15473859
references.citation: Science. 2005 Jan 7;307(5706):127-9
references.pmid: 15637283
references.citation: J Neurosci. 2003 Sep 24;23(25):8673-81
references.pmid: 14507966
references.citation: J Cell Sci. 2010 Jan 15;123(Pt 2):202-12
references.pmid: 20048338
references.citation: Horm Cancer. 2011 Apr;2(2):104-12
references.pmid: 21761333
references.citation: Cell. 2004 Nov 12;119(4):503-16
references.pmid: 15537540
references.citation: Curr Biol. 1996 Dec 1;6(12):1592-4
references.pmid: 8994822
references.citation: Nat Cell Biol. 2008 Jun;10(6):748-51
references.pmid: 18469805
references.citation: Neuron. 2000 Dec;28(3):681-96
references.pmid: 11163259
references.citation: Biochem Biophys Res Commun. 2011 Jun 3;409(2):193-9
references.pmid: 21569763
references.citation: Cell. 2001 May 18;105(4):421-4
references.pmid: 11371339
references.citation: Curr Biol. 2000 Jul 13;10(14):865-8
references.pmid: 10899006
references.citation: Nature. 2007 May 24;447(7143):493-6
references.pmid: 17495931
references.citation: Nat Cell Biol. 2007 Nov;9(11):1294-302
references.pmid: 17922003
references.citation: Mol Biol Cell. 2005 Nov;16(11):5127-40
references.pmid: 16107559
references.citation: Cell. 2008 Jun 13;133(6):1032-42
references.pmid: 18555779
references.citation: Nat Cell Biol. 2011 Jun 12;13(7):771-8
references.pmid: 21666685
references.citation: J Cell Biol. 2011 Aug 8;194(3):377-86
references.pmid: 21825072
references.citation: Nature. 1994 Jul 21;370(6486):216-8
references.pmid: 8028668
references.citation: Nat Cell Biol. 2005 May;7(5):517-24
references.pmid: 15852003
references.citation: Nat Cell Biol. 2000 Nov;2(11):767-75
references.pmid: 11056530
references.citation: J Biol Chem. 2011 Nov 11;286(45):39615-22
references.pmid: 21911489
references.citation: Nat Genet. 2003 Jul;34(3):274-85
references.pmid: 12796778
references.citation: Trends Cell Biol. 1998 Dec;8(12):467-70
references.pmid: 9861667
references.citation: EMBO J. 2007 Mar 21;26(6):1487-98
references.pmid: 17318179
references.citation: Nat Cell Biol. 2011 Oct 03;13(10):1154-60
references.pmid: 21968988
references.citation: J Cell Biol. 2005 Jan 17;168(2):201-7
references.pmid: 15642746
references.citation: Neuron. 2004 Oct 14;44(2):279-93
references.pmid: 15473967
references.citation: Mol Cell. 2004 Aug 13;15(3):317-27
references.pmid: 15304213
references.citation: Nat Cell Biol. 2005 Jul;7(7):686-90
references.pmid: 15965467
references.citation: Mol Biol Cell. 2004 Aug;15(8):3642-57
references.pmid: 15146056
references.citation: Curr Biol. 2003 Mar 4;13(5):364-72
references.pmid: 12620184
references.citation: Annu Rev Cell Dev Biol. 2005;21:411-34
references.pmid: 16212501
references.citation: Nat Cell Biol. 2012 Feb 12;14(3):311-7
references.pmid: 22327364
references.citation: J Cell Biol. 2001 Dec 24;155(7):1159-72
references.pmid: 11756470
references.citation: EMBO J. 2008 Oct 8;27(19):2471-83
references.pmid: 18784752