title: The apical complex couples cell fate and cell survival to cerebral cortical development.
abstract: Cortical development depends upon tightly controlled cell fate and cell survival decisions that generate a functional neuronal population, but the coordination of these two processes is poorly understood. Here we show that conditional removal of a key apical complex protein, Pals1, causes premature withdrawal from the cell cycle, inducing excessive generation of early-born postmitotic neurons followed by surprisingly massive and rapid cell death, leading to the abrogation of virtually the entire cortical structure. Pals1 loss shows exquisite dosage sensitivity, so that heterozygote mutants show an intermediate phenotype on cell fate and cell death. Loss of Pals1 blocks essential cell survival signals, including the mammalian target of rapamycin (mTOR) pathway, while mTORC1 activation partially rescues Pals1 deficiency. These data highlight unexpected roles of the apical complex protein Pals1 in cell survival through interactions with mTOR signaling.
authors.affiliation: Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Seonhee
authors.initials: S
authors.lastname: Kim
authors.forename: Maria K
authors.initials: MK
authors.lastname: Lehtinen
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sessa
authors.forename: Mauro W
authors.initials: MW
authors.lastname: Zappaterra
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: Cho
authors.forename: Dilenny
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Brigid
authors.initials: B
authors.lastname: Boggan
authors.forename: Christina A
authors.initials: CA
authors.lastname: Austin
authors.forename: Jan
authors.initials: J
authors.lastname: Wijnholds
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.forename: Jarema
authors.initials: J
authors.lastname: Malicki
authors.forename: Anthony S
authors.initials: AS
authors.lastname: LaMantia
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018390:Gene Targeting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D009703:Nucleoside-Phosphate Kinase; C499979:Mpp5 protein, mouse
references.citation: J Cell Biol. 2002 Apr 1;157(1):161-72
references.pmid: 11927608
references.citation: Neuron. 2009 Jul 30;63(2):189-202
references.pmid: 19640478
references.citation: Nat Genet. 2002 Jun;31(2):150-7
references.pmid: 11992120
references.citation: Nat Genet. 2004 Mar;36(3):264-70
references.pmid: 14758363
references.citation: Nat Genet. 1999 Oct;23(2):217-21
references.pmid: 10508521
references.citation: Nature. 2002 Oct 31;419(6910):929-34
references.pmid: 12410312
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3196-201
references.pmid: 14963232
references.citation: Genes Dev. 2006 Jun 1;20(11):1511-24
references.pmid: 16705040
references.citation: J Comp Physiol Psychol. 1965 Apr;59:193-201
references.pmid: 14291615
references.citation: Development. 2008 Dec;135(23):3911-21
references.pmid: 18997113
references.citation: Nature. 2005 Jun 30;435(7046):1244-50
references.pmid: 15902206
references.citation: Science. 2002 Jul 19;297(5580):365-9
references.pmid: 12130776
references.citation: Nat Cell Biol. 2003 Feb;5(2):137-42
references.pmid: 12545177
references.citation: Nature. 2001 Feb 8;409(6821):714-20
references.pmid: 11217860
references.citation: Trends Neurosci. 1995 Sep;18(9):379-83
references.pmid: 7482802
references.citation: Science. 2006 Mar 17;311(5767):1609-12
references.pmid: 16543460
references.citation: Nat Neurosci. 2007 Jul;10(7):819-27
references.pmid: 17589506
references.citation: Oncogene. 2006 Oct 19;25(49):6467-79
references.pmid: 16702951
references.citation: Annu Rev Cell Dev Biol. 2007;23:345-73
references.pmid: 17506691
references.citation: J Biol Chem. 2008 Aug 22;283(34):23440-9
references.pmid: 18550519
references.citation: Nat Rev Mol Cell Biol. 2005 Oct;6(10):777-88
references.pmid: 16314867
references.citation: Neuron. 2004 Mar 25;41(6):881-90
references.pmid: 15046721
references.citation: Curr Biol. 2006 Jan 24;16(2):140-9
references.pmid: 16431366
references.citation: J Clin Invest. 2010 Jan;120(1):93-102
references.pmid: 20038815
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):475-81
references.pmid: 16099639
references.citation: Neuron. 2001 Sep 13;31(5):727-41
references.pmid: 11567613
references.citation: Development. 2008 Jan;135(1):11-22
references.pmid: 18032449
references.citation: Neuron. 2003 Dec 18;40(6):1105-18
references.pmid: 14687546
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):596-603
references.pmid: 16226444
references.citation: Hum Mol Genet. 2006 Sep 15;15(18):2659-72
references.pmid: 16885194
references.citation: Nat Neurosci. 2004 Aug;7(8):803-11
references.pmid: 15273690
references.citation: Nat Protoc. 2006;1(3):1552-8
references.pmid: 17406448
references.citation: J Comp Neurol. 2008 May 1;508(1):28-44
references.pmid: 18288691
references.citation: Cereb Cortex. 2009 Oct;19(10):2439-50
references.pmid: 19168665
references.citation: Development. 2006 May;133(9):1735-44
references.pmid: 16571631
references.citation: Nat Neurosci. 2009 Jan;12(1):44-52
references.pmid: 19060896
references.citation: Behav Brain Sci. 2001 Apr;24(2):263-78; discussion 278-308
references.pmid: 11530543
references.citation: EMBO J. 1999 Apr 15;18(8):2196-207
references.pmid: 10205173
references.citation: Nature. 2001 Dec 6;414(6864):638-43
references.pmid: 11740560
references.citation: Nature. 2001 Dec 6;414(6864):634-8
references.pmid: 11740559
references.citation: J Neurosci. 2002 Apr 15;22(8):3161-73
references.pmid: 11943818
references.citation: Development. 2004 Jul;131(13):3133-45
references.pmid: 15175243
references.citation: J Biol Chem. 2000 Apr 14;275(15):11425-31
references.pmid: 10753959
references.citation: Nat Neurosci. 2006 Sep;9(9):1099-107
references.pmid: 16892058
references.citation: Genes Dev. 2004 Mar 1;18(5):559-71
references.pmid: 15037549
references.citation: J Neurosci. 1996 Oct 1;16(19):6183-96
references.pmid: 8815900
references.citation: Development. 2005 Apr;132(7):1675-86
references.pmid: 15743877
references.citation: Development. 2008 May;135(10):1781-90
references.pmid: 18403412
references.citation: Development. 2008 May;135(9):1575-87
references.pmid: 18356248
references.citation: Nat Neurosci. 2004 Feb;7(2):136-44
references.pmid: 14703572
references.citation: Science. 2007 Jul 20;317(5836):372-6
references.pmid: 17641202
references.citation: J Biol Chem. 2002 Jul 26;277(30):27501-9
references.pmid: 12021270
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8204-9
references.pmid: 15928081
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):648-57
references.pmid: 16243506
references.citation: Dev Neurosci. 2006;28(1-2):49-57
references.pmid: 16508303
references.citation: Neurosci Res. 2001 Sep;41(1):51-60
references.pmid: 11535293
references.citation: Hum Mol Genet. 2009 Apr 1;18(7):1252-65
references.pmid: 19150975
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19836-41
references.pmid: 17172441
references.citation: Mol Biol Cell. 2007 Mar;18(3):874-85
references.pmid: 17182851
references.citation: Dev Biol. 2003 Jun 15;258(2):406-18
references.pmid: 12798297
references.citation: Mol Biol Cell. 2004 Apr;15(4):1981-90
references.pmid: 14718565
references.citation: J Neurosci. 2002 Aug 1;22(15):6309-14
references.pmid: 12151506
references.citation: Brain. 1974 Dec;97(4):709-28
references.pmid: 4434190
references.citation: J Cell Biol. 2009 Jun 15;185(6):959-67
references.pmid: 19506035
references.citation: Dev Cell. 2007 May;12(5):767-78
references.pmid: 17488627
references.citation: Curr Opin Cell Biol. 2004 Apr;16(2):195-205
references.pmid: 15196564
references.citation: Hum Mol Genet. 2007 Mar 1;16(5):529-36
references.pmid: 17234746
references.citation: Neuron. 2008 Mar 27;57(6):809-18
references.pmid: 18367082
references.citation: Biochem J. 1994 Nov 1;303 ( Pt 3):701-4
references.pmid: 7980435
references.citation: Genesis. 2007 Feb;45(2):101-6
references.pmid: 17245776
references.citation: Development. 2004 Nov;131(22):5539-50
references.pmid: 15496443
references.citation: Curr Opin Cell Biol. 2008 Dec;20(6):707-15
references.pmid: 18930817
references.citation: Curr Opin Neurobiol. 2003 Feb;13(1):34-41
references.pmid: 12593980