title: ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c.
abstract: Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx(-/Y) mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.
authors: Department of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors: Gaia
authors: G
authors: Colasante
authors: Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Jacqueline C
authors: JC
authors: Simonet
authors: Bioinformatics and Genomics Unit, MBC Centro di Biotecnologie Molecolari, Turin, Italy.
authors: Raffaele
authors: R
authors: Calogero
authors: Institute of Genetics and Byophisics "A. B. T" CNR, Naples 80131, Italy and.
authors: Stefania
authors: S
authors: Crispi
authors: Department of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors: Alessandro
authors: A
authors: Sessa
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Ginam
authors: G
authors: Cho
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Jeffrey A
authors: JA
authors: Golden
authors: Department of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors: Vania
authors: V
authors: Broccoli
mesh_terms: D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002540:Cerebral Cortex / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis / Q000502:physiology; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009830:Olfactory Bulb / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: C469265:ARX protein, mouse; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018398:Homeodomain Proteins; D014157:Transcription Factors
keywords: TBR2; cell cycle; forebrain development; neurodevelopmental disorders; neurogenesis
references: Genes Dev. 2006 Jun 1;20(11):1511-24
references: 16705040
references: Development. 2012 Feb;139(3):475-87
references: 22223678
references: Science. 2002 Jul 19;297(5580):365-9
references: 12130776
references: Hum Mol Genet. 2008 Dec 1;17(23):3740-60
references: 18799476
references: Genes Dev. 1999 Jun 15;13(12):1501-12
references: 10385618
references: Nat Rev Neurosci. 2007 Jun;8(6):427-37
references: 17514196
references: Genes Dev. 2003 Oct 15;17(20):2591-603
references: 14561778
references: Nat Genet. 2002 Nov;32(3):359-69
references: 12379852
references: Genesis. 2007 Apr;45(4):208-17
references: 17417802
references: J Comp Neurol. 1998 Jul 27;397(2):181-98
references: 9658283
references: Eur J Neurosci. 2006 Feb;23(4):869-76
references: 16519652
references: Nature. 1999 Oct 14;401(6754):670-7
references: 10537105
references: Neuron. 2008 Oct 9;60(1):56-69
references: 18940588
references: Histochemistry. 1993 Dec;100(6):431-40
references: 7512949
references: Genes Dev. 1993 Nov;7(11):2120-34
references: 7901121
references: Development. 2001 Jun;128(11):1983-93
references: 11493521
references: Dev Biol. 2009 Oct 1;334(1):59-71
references: 19627984
references: Dev Dyn. 2004 Nov;231(3):631-9
references: 15376319
references: J Neurosci. 2008 May 28;28(22):5794-805
references: 18509041
references: J Biol Chem. 2007 Apr 27;282(17):12537-46
references: 17331942
references: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references: 11752295
references: Neuroscience. 2007 Apr 25;146(1):236-47
references: 17331656
references: Cereb Cortex. 2011 Aug;21(8):1840-56
references: 21245411
references: J Neurosci. 1995 Sep;15(9):6046-57
references: 7666188
references: Biochem Biophys Res Commun. 2000 Apr 21;270(3):978-82
references: 10772936
references: Nat Neurosci. 2002 Aug;5(8):737-45
references: 12118260
references: PLoS One. 2011;6(9):e25181
references: 21966449
references: Hum Mol Genet. 2012 Mar 1;21(5):1090-8
references: 22108177
references: J Biol Chem. 2007 Jan 5;282(1):390-6
references: 17092932
references: Cereb Cortex. 2004 Dec;14(12):1408-20
references: 15238450
references: Genes Dev. 2008 Sep 15;22(18):2479-84
references: 18794345
references: Dev Neurobiol. 2012 Jun;72(6):821-42
references: 22076965
references: J Neurosci. 2008 Oct 15;28(42):10674-86
references: 18923043
references: J Comp Neurol. 2004 Nov 8;479(2):168-80
references: 15452856
references: Curr Opin Genet Dev. 2006 Jun;16(3):308-16
references: 16650978
references: J Neurosci. 2007 Apr 25;27(17):4786-98
references: 17460091