title: A FOXO-Pak1 transcriptional pathway controls neuronal polarity.
abstract: Neuronal polarity is essential for normal brain development and function. However, cell-intrinsic mechanisms that govern the establishment of neuronal polarity remain to be identified. Here, we report that knockdown of endogenous FOXO proteins in hippocampal and cerebellar granule neurons, including in the rat cerebellar cortex in vivo, reveals a requirement for the FOXO transcription factors in the establishment of neuronal polarity. The FOXO transcription factors, including the brain-enriched protein FOXO6, play a critical role in axo-dendritic polarization of undifferentiated neurites, and hence in a switch from unpolarized to polarized neuronal morphology. We also identify the gene encoding the protein kinase Pak1, which acts locally in neuronal processes to induce polarity, as a critical direct target gene of the FOXO transcription factors. Knockdown of endogenous Pak1 phenocopies the effect of FOXO knockdown on neuronal polarity. Importantly, exogenous expression of Pak1 in the background of FOXO knockdown in both primary neurons and postnatal rat pups in vivo restores the polarized morphology of neurons. These findings define the FOXO proteins and Pak1 as components of a cell-intrinsic transcriptional pathway that orchestrates neuronal polarity, thus identifying a novel function for the FOXO transcription factors in a unique aspect of neural development.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: de la Torre-Ubieta
authors.forename: Brice
authors.initials: B
authors.lastname: Gaudillière
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.forename: Yoshiho
authors.initials: Y
authors.lastname: Ikeuchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada
authors.forename: Sara
authors.initials: S
authors.lastname: DiBacco
authors.forename: Judith
authors.initials: J
authors.lastname: Stegmüller
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.forename: Dervis A
authors.initials: DA
authors.lastname: Salih
authors.forename: David
authors.initials: D
authors.lastname: Rowitch
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C515906:Pak1 protein, rat; D054462:p21-Activated Kinases
references.citation: Science. 2004 Jan 9;303(5655):197-202
references.pmid: 14716005
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9882-7
references.pmid: 17535924
references.citation: Neuron. 2006 Mar 16;49(6):797-804
references.pmid: 16543128
references.citation: Nat Neurosci. 2004 Sep;7(9):923-9
references.pmid: 15286792
references.citation: Cell. 2007 May 4;129(3):549-63
references.pmid: 17482548
references.citation: Annu Rev Neurosci. 1994;17:267-310
references.pmid: 8210176
references.citation: J Neurobiol. 1997 Feb;32(2):223-36
references.pmid: 9032664
references.citation: Mol Cell. 2004 May 21;14(4):416-8
references.pmid: 15149589
references.citation: Science. 2005 Feb 11;307(5711):929-32
references.pmid: 15705853
references.citation: Cell. 2007 Jan 26;128(2):309-23
references.pmid: 17254969
references.citation: Nature. 2005 Aug 4;436(7051):704-8
references.pmid: 16079847
references.citation: Biochem J. 2005 Nov 1;391(Pt 3):623-9
references.pmid: 15987244
references.citation: Annu Rev Biochem. 2003;72:743-81
references.pmid: 12676796
references.citation: Cell. 2003 Jan 10;112(1):63-75
references.pmid: 12526794
references.citation: Trends Biochem Sci. 2002 Jul;27(7):352-60
references.pmid: 12114024
references.citation: Cell. 2004 May 14;117(4):421-6
references.pmid: 15137936
references.citation: Curr Biol. 2007 Feb 20;17(4):R113-4
references.pmid: 17307039
references.citation: Cell. 1999 Mar 19;96(6):857-68
references.pmid: 10102273
references.citation: Sci STKE. 2003 Mar 04;2003(172):RE5
references.pmid: 12621150
references.citation: Nat Rev Neurosci. 2007 Mar;8(3):194-205
references.pmid: 17311006
references.citation: J Biol Chem. 2002 Nov 29;277(48):46442-6
references.pmid: 12235147
references.citation: Neuron. 2005 Oct 6;48(1):45-62
references.pmid: 16202708
references.citation: Cell. 2005 Jan 14;120(1):137-49
references.pmid: 15652488
references.citation: Neuron. 2004 Jun 24;42(6):897-912
references.pmid: 15207235
references.citation: J Biol Chem. 2004 Feb 13;279(7):6196-203
references.pmid: 14645234
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11489-94
references.pmid: 17592139
references.citation: J Neurosci. 2007 Aug 8;27(32):8604-15
references.pmid: 17687038
references.citation: Curr Opin Neurobiol. 2004 Oct;14(5):551-7
references.pmid: 15464887
references.citation: Trends Endocrinol Metab. 2005 May-Jun;16(4):183-9
references.pmid: 15860415
references.citation: Science. 2006 Feb 17;311(5763):1012-7
references.pmid: 16484498
references.citation: Biol Cell. 2008 Feb;100(2):97-108
references.pmid: 18199048
references.citation: Cell. 2005 Jan 14;120(1):123-35
references.pmid: 15652487
references.citation: Cell. 2006 Jun 2;125(5):987-1001
references.pmid: 16751106
references.citation: Mol Cell. 2002 May;9(5):1005-16
references.pmid: 12049737
references.citation: Neuron. 2004 Jan 22;41(2):229-41
references.pmid: 14741104
references.citation: Nat Rev Cancer. 2006 Jun;6(6):459-71
references.pmid: 16723992
references.citation: Mol Neurobiol. 2008 Apr-Jun;37(2-3):187-202
references.pmid: 18649038
references.citation: Nat Cell Biol. 1999 Sep;1(5):253-9
references.pmid: 10559936
references.citation: Science. 2008 Mar 21;319(5870):1665-8
references.pmid: 18356527
references.citation: Neuron. 2003 Oct 9;40(2):229-42
references.pmid: 14556706
references.citation: Mol Cell Neurosci. 2007 Mar;34(3):281-7
references.pmid: 17223572
references.citation: Nat Rev Immunol. 2004 Nov;4(11):889-99
references.pmid: 15516968
references.citation: Trends Neurosci. 2005 Nov;28(11):596-601
references.pmid: 16168498
references.citation: Cell. 2003 Mar 21;112(6):805-18
references.pmid: 12654247
references.citation: Science. 2004 Feb 13;303(5660):1026-30
references.pmid: 14716021
references.citation: Neuron. 2006 May 4;50(3):389-400
references.pmid: 16675394
references.citation: Neuron. 2004 Jun 10;42(5):773-87
references.pmid: 15182717
references.citation: Cell. 2007 May 4;129(3):565-77
references.pmid: 17482549
references.citation: J Neurosci Res. 1993 Aug 1;35(5):567-76
references.pmid: 8377226
references.citation: Nature. 2001 Oct 18;413(6857):744-7
references.pmid: 11607034
references.citation: Biochem J. 2004 Jun 1;380(Pt 2):297-309
references.pmid: 15005655
references.citation: Nat Rev Neurosci. 2007 May;8(5):331-40
references.pmid: 17453014
references.citation: Gene Expr Patterns. 2006 Jan;6(2):134-40
references.pmid: 16326148
references.citation: Cereb Cortex. 2009 Apr;19(4):861-75
references.pmid: 18701438
references.citation: J Biol Chem. 2003 Sep 19;278(38):35959-67
references.pmid: 12857750