title: Huntingtin regulates mammary stem cell division and differentiation.
abstract: Little is known about the mechanisms of mitotic spindle orientation during mammary gland morphogenesis. Here, we report the presence of huntingtin, the protein mutated in Huntington's disease, in mouse mammary basal and luminal cells throughout mammogenesis. Keratin 5-driven depletion of huntingtin results in a decreased pool and specification of basal and luminal progenitors, and altered mammary morphogenesis. Analysis of mitosis in huntingtin-depleted basal progenitors reveals mitotic spindle misorientation. In mammary cell culture, huntingtin regulates spindle orientation in a dynein-dependent manner. Huntingtin is targeted to spindle poles through its interaction with dynein and promotes the accumulation of NUMA and LGN. Huntingtin is also essential for the cortical localization of dynein, dynactin, NUMA, and LGN by regulating their kinesin 1-dependent trafficking along astral microtubules. We thus suggest that huntingtin is a component of the pathway regulating the orientation of mammary stem cell division, with potential implications for their self-renewal and differentiation properties.
authors.affiliation: Institut Curie, Orsay 91405, France ; CNRS UMR 3306, Orsay 91405, France ; INSERM U1005, Orsay 91405, France.
authors.forename: Salah
authors.initials: S
authors.lastname: Elias
authors.affiliation: Institut Curie, Orsay 91405, France ; CNRS UMR 3306, Orsay 91405, France ; INSERM U1005, Orsay 91405, France.
authors.forename: Morgane S
authors.initials: MS
authors.lastname: Thion
authors.affiliation: Institut Curie, Orsay 91405, France ; CNRS UMR 3306, Orsay 91405, France ; INSERM U1005, Orsay 91405, France.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institut Curie, Orsay 91405, France ; CNRS UMR 3306, Orsay 91405, France ; INSERM U1005, Orsay 91405, France.
authors.forename: Cristovao Marques
authors.initials: CM
authors.lastname: Sousa
authors.affiliation: Institut Curie, Orsay 91405, France ; CNRS UMR 3306, Orsay 91405, France ; INSERM U1005, Orsay 91405, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Lasgi
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris 75005, France ; INSERM U1024, Paris 75005, France ; CNRS UMR 8197, Paris 75005, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Morin
authors.affiliation: Institut Curie, Orsay 91405, France ; CNRS UMR 3306, Orsay 91405, France ; INSERM U1005, Orsay 91405, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D002460:Cell Line; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis; D009024:Morphogenesis; D046912:Multiprotein Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference; D008941:Spindle Apparatus; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D000072159:Dynactin Complex; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C511012:Ktn1 protein, mouse; C502655:LGN protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C489080:Numa1 protein, mouse; D004398:Dyneins
references.citation: Nature. 2010 Jun 10;465(7299):803-7
references.pmid: 20445538
references.citation: Cell Death Differ. 2010 Oct;17(10):1600-12
references.pmid: 20379195
references.citation: EMBO Mol Med. 2013 Feb;5(2):309-25
references.pmid: 23300147
references.citation: Cell. 2004 Jul 9;118(1):127-38
references.pmid: 15242649
references.citation: Mol Cell Biol. 2002 May;22(9):3089-102
references.pmid: 11940666
references.citation: Int J Dev Biol. 2011;55(7-9):763-71
references.pmid: 21948739
references.citation: EMBO J. 2008 Aug 6;27(15):2124-34
references.pmid: 18615096
references.citation: Mol Cell Biol. 2010 Jul;30(14):3519-30
references.pmid: 20479129
references.citation: Nat Rev Mol Cell Biol. 2011 Aug 10;12(9):581-93
references.pmid: 21829222
references.citation: Microsc Res Tech. 2001 Jan 15;52(2):155-62
references.pmid: 11169863
references.citation: Nat Cell Biol. 2012 Feb 12;14(3):311-7
references.pmid: 22327364
references.citation: Curr Biol. 2013 Apr 8;23(7):588-93
references.pmid: 23523245
references.citation: J Cell Biol. 2011 Apr 4;193(1):141-54
references.pmid: 21444683
references.citation: Dev Cell. 2005 Apr;8(4):461-5
references.pmid: 15809029
references.citation: Nat Cell Biol. 2000 Nov;2(11):784-91
references.pmid: 11056532
references.citation: Dev Cell. 2013 Aug 26;26(4):369-80
references.pmid: 23987511
references.citation: Nat Cell Biol. 2009 Apr;11(4):365-74
references.pmid: 19337318
references.citation: Dev Growth Differ. 2012 Apr;54(3):277-86
references.pmid: 22524601
references.citation: Breast Cancer Res. 2012 Oct 22;14(5):R134
references.pmid: 23088371
references.citation: Nature. 2014 Feb 20;506(7488):322-7
references.pmid: 24463516
references.citation: J Biol Chem. 2006 Feb 10;281(6):3552-9
references.pmid: 16339760
references.citation: Nature. 2011 Feb 17;470(7334):353-8
references.pmid: 21331036
references.citation: Cell Stem Cell. 2010 Feb 5;6(2):175-81
references.pmid: 20144789
references.citation: Exp Neurol. 1998 Jul;152(1):34-40
references.pmid: 9682010
references.citation: J Cell Biol. 2010 Apr 19;189(2):275-88
references.pmid: 20385777
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2989-94
references.pmid: 20133621
references.citation: Nature. 2010 Jun 10;465(7299):798-802
references.pmid: 20383121
references.citation: EMBO J. 2011 Nov 08;30(24):4858-9
references.pmid: 22068053
references.citation: Mol Brain. 2010 Jun 01;3:17
references.pmid: 20515468
references.citation: Curr Opin Neurobiol. 2012 Oct;22(5):737-46
references.pmid: 22554882
references.citation: J Neurosci. 2007 Mar 28;27(13):3571-83
references.pmid: 17392473
references.citation: Curr Biol. 2013 Apr 8;23(7):581-7
references.pmid: 23523246
references.citation: Genesis. 2004 May;39(1):52-7
references.pmid: 15124227
references.citation: Cell Stem Cell. 2008 Oct 9;3(4):429-41
references.pmid: 18940734
references.citation: Nat Cell Biol. 2008 Jun;10(6):716-22
references.pmid: 18469806
references.citation: Nat Cell Biol. 2008 Jan;10(1):93-101
references.pmid: 18084280
references.citation: Cell. 2009 Sep 18;138(6):1083-95
references.pmid: 19766563
references.citation: Neuron. 2010 Aug 12;67(3):392-406
references.pmid: 20696378
references.citation: Dev Growth Differ. 2012 Apr;54(3):287-305
references.pmid: 22524602
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10045-50
references.pmid: 17548833
references.citation: J Cell Biol. 2012 Oct 1;199(1):97-110
references.pmid: 23027904
references.citation: Nature. 2012 Aug 23;488(7412):527-30
references.pmid: 22854777
references.citation: Nat Neurosci. 2007 Nov;10(11):1440-8
references.pmid: 17934458
references.citation: Neuron. 2012 Jul 12;75(1):41-57
references.pmid: 22794259
references.citation: Nature. 2006 Jan 5;439(7072):84-8
references.pmid: 16397499
references.citation: Nat Genet. 2000 Nov;26(3):300-6
references.pmid: 11062468
references.citation: Cell Rep. 2013 Jul 11;4(1):110-23
references.pmid: 23810554
references.citation: Development. 2012 Sep;139(17):3147-56
references.pmid: 22833129
references.citation: J Microsc. 2006 Dec;224(Pt 3):213-32
references.pmid: 17210054
references.citation: Dev Cell. 2011 Jul 19;21(1):102-19
references.pmid: 21763612