title: Prenatal β-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.
abstract: Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a β-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the β-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.
authors.affiliation: Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Belinson
authors.affiliation: Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nakatani
authors.affiliation: Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Babineau
authors.affiliation: Department of Life Sciences, Ben-Gurion University at the Negev, Beer-Sheva, Israel.
authors.forename: R Y
authors.initials: RY
authors.lastname: Birnbaum
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Ellegood
authors.affiliation: Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bershteyn
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: McEvilly
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institute of Health, Baltimore, MD, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Long
authors.affiliation: Deparment of Cell and Molecular Biology, Institute for Regenerative Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Willert
authors.affiliation: Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: O D
authors.initials: OD
authors.lastname: Klein
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ahituv
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: J P
authors.initials: JP
authors.lastname: Lerch
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Rosenfeld
authors.affiliation: Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San Francisco School of Medicine, San Francisco, CA, USA.|Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D000072261:Dishevelled Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology; D058953:Neural Stem Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D050809:POU Domain Factors / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013239:Stereotyped Behavior / Q000502:physiology; D019956:Stereotypic Movement Disorder / Q000235:genetics* / Q000503:physiopathology*; D020825:T-Box Domain Proteins / Q000378:metabolism / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C000606585:Dvl3 protein, mouse; C491198:Eomes protein, mouse; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D010750:Phosphoproteins; D020825:T-Box Domain Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C074066:Pou3f2 protein, mouse
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3299-304
references.pmid: 12626757
references.citation: Magn Reson Med. 1999 Sep;42(3):515-25
references.pmid: 10467296
references.citation: Neuroimage. 2008 Aug 1;42(1):60-9
references.pmid: 18502665
references.citation: Behav Brain Res. 2009 Dec 14;205(1):123-31
references.pmid: 19540269
references.citation: Genes Dev. 1995 Dec 15;9(24):3122-35
references.pmid: 8543156
references.citation: J Clin Invest. 2015 Aug 3;125(8):2914-23
references.pmid: 26237041
references.citation: J Comp Neurol. 2004 Nov 8;479(2):168-80
references.pmid: 15452856
references.citation: Cereb Cortex. 2012 May;22(5):1025-37
references.pmid: 21784971
references.citation: Nature. 2011 Nov 23;480(7375):63-8
references.pmid: 22113615
references.citation: Neuroimage. 2008 Jan 1;39(1):32-9
references.pmid: 17942324
references.citation: Magn Reson Med. 2003 Jan;49(1):158-67
references.pmid: 12509832
references.citation: Science. 2002 Jul 19;297(5580):365-9
references.pmid: 12130776
references.citation: Brain Res Mol Brain Res. 2004 Dec 6;132(1):38-50
references.pmid: 15548427
references.citation: Curr Protoc Neurosci. 2011 Jul;Chapter 8:Unit 8.26
references.pmid: 21732314
references.citation: Diabetes. 2003 Mar;52(3):588-95
references.pmid: 12606497
references.citation: Physiol Genomics. 2006 Jan 12;24(2):154-62
references.pmid: 16410543
references.citation: Psychopharmacology (Berl). 2009 Jun;204(2):361-73
references.pmid: 19189082
references.citation: Nat Protoc. 2006;1(1):179-85
references.pmid: 17406230
references.citation: Neuroimage. 2002 Apr;15(4):870-8
references.pmid: 11906227
references.citation: J Biol Chem. 2004 Oct 1;279(40):41846-57
references.pmid: 15262984
references.citation: Cell. 2013 Nov 21;155(5):1008-21
references.pmid: 24267887
references.citation: Neuropharmacology. 2012 Nov;63(6):1028-41
references.pmid: 22841957
references.citation: Neuroimage. 2007 May 1;35(4):1424-33
references.pmid: 17408971
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10
references.pmid: 16381825
references.citation: Cereb Cortex. 2013 Nov;23(11):2632-43
references.pmid: 22892427
references.citation: Mol Autism. 2012 Oct 19;3(1):10
references.pmid: 23083465
references.citation: JAMA. 2011 Nov 9;306(18):2001-10
references.pmid: 22068992
references.citation: J Neurosci. 2013 Mar 6;33(10):4216-33
references.pmid: 23467340
references.citation: Hum Mutat. 2012 Apr;33(4):728-40
references.pmid: 22290657
references.citation: Hum Brain Mapp. 2014 Feb;35(2):567-80
references.pmid: 23118015
references.citation: Autism Res. 2012 Oct;5(5):340-51
references.pmid: 22933354
references.citation: Genes Brain Behav. 2004 Feb;3(1):51-62
references.pmid: 14960015
references.citation: Cell. 2013 Nov 21;155(5):997-1007
references.pmid: 24267886
references.citation: Cell. 2013 Oct 24;155(3):621-35
references.pmid: 24243019
references.citation: Cell. 1997 Sep 5;90(5):895-905
references.pmid: 9298901
references.citation: J Biol Chem. 2009 Mar 20;284(12):8160-73
references.pmid: 19147497
references.citation: PLoS Biol. 2008 Jul 1;6(7):e159
references.pmid: 18597554
references.citation: Development. 2004 Jun;131(12):2791-801
references.pmid: 15142975
references.citation: Development. 2006 May;133(9):1767-78
references.pmid: 16571627
references.citation: Cancer Res. 2008 Oct 1;68(19):7788-94
references.pmid: 18829533
references.citation: J Neurochem. 2005 Mar;92(6):1550-3
references.pmid: 15748172
references.citation: Mech Dev. 1997 Jan;61(1-2):113-25
references.pmid: 9076682
references.citation: Neuron. 2013 Jun 5;78(5):895-909
references.pmid: 23664552
references.citation: Nature. 2011 May 25;474(7351):380-4
references.pmid: 21614001
references.citation: PLoS One. 2012;7(4):e35892
references.pmid: 22540008
references.citation: PLoS Genet. 2008 Nov;4(11):e1000259
references.pmid: 19008950
references.citation: Autism Res. 2014 Feb;7(1):124-37
references.pmid: 24151012
references.citation: J Neurosci. 2008 Feb 13;28(7):1613-24
references.pmid: 18272682
references.citation: Mol Cell Biol. 2004 Apr;24(7):2915-22
references.pmid: 15024079
references.citation: Cell. 2011 Jul 8;146(1):18-36
references.pmid: 21729779
references.citation: Development. 1995 Jun;121(6):1637-47
references.pmid: 7600981
references.citation: Pediatr Res. 2011 May;69(5 Pt 2):34R-40R
references.pmid: 21289542
references.citation: Science. 2002 Feb 22;295(5559):1528-32
references.pmid: 11859196
references.citation: J Neurosci. 2011 Feb 2;31(5):1676-87
references.pmid: 21289176
references.citation: Brain. 2015 May;138(Pt 5):1394-409
references.pmid: 25765326
references.citation: J Neurosci. 2002 Sep 1;22(17):7548-57
references.pmid: 12196578
references.citation: Development. 2010 Apr;137(7):1035-44
references.pmid: 20215343
references.citation: Development. 2002 Dec;129(24):5827-38
references.pmid: 12421720
references.citation: J Comp Neurol. 2003 May 26;460(2):266-79
references.pmid: 12687690
references.citation: PLoS Genet. 2012;8(3):e1002592
references.pmid: 22457638
references.citation: Neuron. 2008 Oct 9;60(1):56-69
references.pmid: 18940588
references.citation: Cell. 2014 Jul 3;158(1):198-212
references.pmid: 24995986
references.citation: Mol Psychiatry. 2015 Feb;20(1):118-25
references.pmid: 25199916
references.citation: Neuroimage. 2013 Sep;78:196-203
references.pmid: 23587687
references.citation: Neuron. 2002 Aug 1;35(3):489-505
references.pmid: 12165471
references.citation: Dev Biol. 2007 Sep 15;309(2):285-97
references.pmid: 17706960
references.citation: Magn Reson Med. 2005 Sep;54(3):532-7
references.pmid: 16086298
references.citation: Dev Cell. 2006 Dec;11(6):831-44
references.pmid: 17141158
references.citation: Mol Autism. 2014 Nov 20;5:53
references.pmid: 25908951
references.citation: Mol Cell Biol. 2002 Feb;22(4):1172-83
references.pmid: 11809808