title: Tis21 is required for adult neurogenesis in the subventricular zone and for olfactory behavior regulating cyclins, BMP4, Hes1/5 and Ids.
abstract: Bone morphogenic proteins (BMPs) and the Notch pathway regulate quiescence and self-renewal of stem cells of the subventricular zone (SVZ), an adult neurogenic niche. Here we analyze the role at the intersection of these pathways of Tis21 (Btg2/PC3), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells. In Tis21-null SVZ and cultured neurospheres, we observed a strong decrease in the expression of BMP4 and its effectors Smad1/8, while the Notch anti-neural mediators Hes1/5 and the basic helix-loop-helix (bHLH) inhibitors Id1-3 increased. Consistently, expression of the proneural bHLH gene NeuroD1 decreased. Moreover, cyclins D1/2, A2, and E were strongly up-regulated. Thus, in the SVZ Tis21 activates the BMP pathway and inhibits the Notch pathway and the cell cycle. Correspondingly, the Tis21-null SVZ stem cells greatly increased; nonetheless, the proliferating neuroblasts diminished, whereas the post-mitotic neuroblasts paradoxically accumulated in SVZ, failing to migrate along the rostral migratory stream to the olfactory bulb. The ability, however, of neuroblasts to migrate from SVZ explants was not affected, suggesting that Tis21-null neuroblasts do not migrate to the olfactory bulb because of a defect in terminal differentiation. Notably, BMP4 addition or Id3 silencing rescued the defective differentiation observed in Tis21-null neurospheres, indicating that they mediate the Tis21 pro-differentiative action. The reduced number of granule neurons in the Tis21-null olfactory bulb led to a defect in olfactory detection threshold, without effect on olfactory memory, also suggesting that within olfactory circuits new granule neurons play a primary role in odor sensitivity rather than in memory.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Farioli-Vecchioli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Saraulli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy ; Department of Psychology and "Daniel Bovet" Center, Sapienza University of Rome Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cannas
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy ; Department of Psychology and "Daniel Bovet" Center, Sapienza University of Rome Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Alessandro
authors.affiliation: Institute of Translational Pharmacology, National Research Council, Fondazione EBRI Rome, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scardigli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Leonardi
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Cinà
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy ; Libera Università Maria Sartissima Assunta Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Costanzi
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattera
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy ; Department of Psychology and "Daniel Bovet" Center, Sapienza University of Rome Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cestari
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia Rome, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
keywords: Btg2; Hes1/5; Id3; adult neurogenesis; bone morphogenic proteins; olfactory memory; stem cells; subventricular zone
references.citation: Front Neurosci. 2009 Nov 16;3:51
references.pmid: 20582278
references.citation: J Biol Chem. 2011 Feb 18;286(7):5691-707
references.pmid: 21127072
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Virol. 2007 Mar;81(6):2614-23
references.pmid: 17192305
references.citation: Histol Histopathol. 2000 Apr;15(2):603-18
references.pmid: 10809382
references.citation: J Neurosci. 2009 Jul 8;29(27):8704-14
references.pmid: 19587277
references.citation: J Neurosci. 2008 Jan 9;28(2):434-46
references.pmid: 18184786
references.citation: Dev Growth Differ. 2008 Jun;50 Suppl 1:S97-103
references.pmid: 18430159
references.citation: Nat Neurosci. 2008 Oct;11(10):1153-61
references.pmid: 18758458
references.citation: Front Cell Neurosci. 2013 May 14;7:59
references.pmid: 23734097
references.citation: Chem Senses. 2001 Jul;26(6):663-72
references.pmid: 11473932
references.citation: Front Neurosci. 2012 Aug 30;6:124
references.pmid: 22969701
references.citation: Development. 2005 Dec;132(24):5503-14
references.pmid: 16314487
references.citation: Front Cell Neurosci. 2013 Jan 18;6:70
references.pmid: 23346046
references.citation: J Neurosci. 2012 Apr 18;32(16):5654-66
references.pmid: 22514327
references.citation: FASEB J. 2007 Jul;21(9):2215-25
references.pmid: 17371797
references.citation: Science. 1994 May 20;264(5162):1145-8
references.pmid: 8178174
references.citation: J Neurosci. 1997 Jul 1;17(13):5046-61
references.pmid: 9185542
references.citation: Development. 2005 Jan;132(2):335-44
references.pmid: 15604099
references.citation: J Neurosci. 2008 Apr 9;28(15):3966-75
references.pmid: 18400896
references.citation: J Neurosci. 2010 Oct 13;30(41):13794-807
references.pmid: 20943920
references.citation: PLoS One. 2009 Sep 15;4(9):e7017
references.pmid: 19753118
references.citation: Annu Rev Pharmacol Toxicol. 1999;39:295-312
references.pmid: 10331086
references.citation: J Neurosci. 2009 Dec 2;29(48):15245-57
references.pmid: 19955377
references.citation: J Neurosci. 2010 Aug 4;30(31):10484-92
references.pmid: 20685991
references.citation: Nature. 2010 Jan 21;463(7279):374-8
references.pmid: 20090754
references.citation: Dev Cell. 2007 Aug;13(2):283-97
references.pmid: 17681138
references.citation: J Neurosci. 2007 Sep 12;27(37):9951-61
references.pmid: 17855609
references.citation: Nat Neurosci. 2012 Jan 15;15(3):373-80, S1-2
references.pmid: 22246438
references.citation: EMBO J. 2004 Nov 10;23(22):4495-505
references.pmid: 15496983
references.citation: Neuron. 1997 May;18(5):779-91
references.pmid: 9182802
references.citation: Curr Opin Cell Biol. 2009 Dec;21(6):733-40
references.pmid: 19783418
references.citation: J Neurosci. 2004 Mar 31;24(13):3355-69
references.pmid: 15056715
references.citation: Neuron. 2000 Dec;28(3):713-26
references.pmid: 11163261
references.citation: J Neurosci. 2000 May 15;20(10):3714-24
references.pmid: 10804213
references.citation: Mol Cell Biol. 2000 Mar;20(5):1797-815
references.pmid: 10669755
references.citation: Nature. 2010 Sep 16;467(7313):323-7
references.pmid: 20844536
references.citation: Mech Dev. 1994 Aug;47(2):127-37
references.pmid: 7811636
references.citation: Genes Cells. 2002 Dec;7(12):1191-204
references.pmid: 12485160
references.citation: PLoS One. 2007 Nov 14;2(11):e1169
references.pmid: 18000541
references.citation: PLoS One. 2009 Dec 17;4(12):e8339
references.pmid: 20020054
references.citation: J Neurosci. 2010 Mar 3;30(9):3489-98
references.pmid: 20203209
references.citation: Neuron. 1993 Jul;11(1):173-89
references.pmid: 8338665
references.citation: J Neurosci. 2004 Sep 22;24(38):8354-65
references.pmid: 15385618
references.citation: Trends Neurosci. 2005 May;28(5):248-54
references.pmid: 15866199
references.citation: Int J Dev Biol. 2009;53(7):895-908
references.pmid: 19598111
references.citation: Mol Cell Biol. 2004 Dec;24(23):10256-62
references.pmid: 15542835
references.citation: Neuron. 2002 Dec 19;36(6):1021-34
references.pmid: 12495619
references.citation: J Comp Neurol. 1969 Dec;137(4):433-57
references.pmid: 5361244
references.citation: Semin Cell Dev Biol. 2006 Aug;17(4):411-23
references.pmid: 16765614
references.citation: Oncogene. 2001 Dec 20;20(58):8290-8
references.pmid: 11840321
references.citation: Cytokine Growth Factor Rev. 2005 Jun;16(3):251-63
references.pmid: 15871923
references.citation: Gene. 2008 May 15;414(1-2):95-105
references.pmid: 18372118
references.citation: Development. 2007 Apr;134(7):1243-51
references.pmid: 17329370
references.citation: J Neurosci. 2012 Oct 31;32(44):15547-64
references.pmid: 23115191
references.citation: Cell. 2008 Feb 22;132(4):645-60
references.pmid: 18295581
references.citation: Nat Neurosci. 2009 Sep;12(9):1090-2
references.pmid: 19701197
references.citation: Nature. 1999 Oct 14;401(6754):670-7
references.pmid: 10537105
references.citation: Mech Dev. 2002 Jun;114(1-2):153-9
references.pmid: 12175503
references.citation: J Neurosci. 2009 Jun 24;29(25):7966-77
references.pmid: 19553437
references.citation: Neuron. 2004 Mar 4;41(5):683-6
references.pmid: 15003168
references.citation: J Exp Med. 2011 May 9;208(5):937-48
references.pmid: 21482697
references.citation: Cell. 1999 Jun 11;97(6):703-16
references.pmid: 10380923
references.citation: PLoS Biol. 2008 Oct 7;6(10):e246
references.pmid: 18842068
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1823-8
references.pmid: 10677540
references.citation: Cell Stem Cell. 2010 Jul 2;7(1):78-89
references.pmid: 20621052
references.citation: Nat Neurosci. 2008 Aug;11(8):888-93
references.pmid: 18587391
references.citation: Development. 2004 Nov;131(22):5539-50
references.pmid: 15496443
references.citation: Trends Neurosci. 2011 Jan;34(1):20-30
references.pmid: 20980064
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4639-44
references.pmid: 10200315
references.citation: J Neurosci. 2002 Jul 15;22(14):6106-13
references.pmid: 12122071
references.citation: J Neurosci. 2008 Mar 5;28(10):2383-93
references.pmid: 18322085
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):678-89
references.pmid: 16921404
references.citation: Curr Top Behav Neurosci. 2013;15:49-72
references.pmid: 22976274
references.citation: Annu Rev Physiol. 2013;75:339-63
references.pmid: 23190074