title: Regulation of the protocadherin Celsr3 gene and its role in globus pallidus development and connectivity.
abstract: The globus pallidus (GP) is a central component of basal ganglia whose malfunctions cause a variety of neuropsychiatric disorders as well as cognitive impairments in neurodegenerative diseases such as Parkinson's disease. Here we report that the protocadherin gene Celsr3 is regulated by the insulator CCCTC-binding factor (CTCF) and the repressor neuron-restrictive silencer factor (NRSF, also known as REST) and is required for the development and connectivity of GP. Specifically, CTCF/cohesin and NRSF inhibit the expression of Celsr3 through specific binding to its promoter. In addition, we found that the Celsr3 promoter interacts with CTCF/cohesin-occupied neighboring promoters. In Celsr3 knockout mice, we found that the ventral GP is occupied by aberrant calbindin-positive cholinergic neurons ectopic from the nucleus basalis of Meynert. Furthermore, the guidepost cells for thalamocortical axonal development are missing in the caudal GP. Finally, axonal connections of GP with striatum, subthalamic nucleus, substantia nigra, and raphe are compromised. These data reveal the essential role of Celsr3 in GP development in the basal forebrain and shed light on the mechanisms of the axonal defects caused by the Celsr3 deletion.
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhilian
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yuanxiao
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Center, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China qwu123@gmail.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005917:Globus Pallidus / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000196:embryology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D015820:Cadherins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C444454:Celsr3 protein, mouse
references.citation: Genome Biol. 2009;10(3):R25
references.pmid: 19261174
references.citation: Methods. 2012 Nov;58(3):221-30
references.pmid: 22609568
references.citation: J Neurosci. 2010 Jul 14;30(28):9392-401
references.pmid: 20631168
references.citation: J Neurosci. 1996 May 15;16(10):3219-35
references.pmid: 8627360
references.citation: Nucleic Acids Res. 2013 Jul;41(13):e132
references.pmid: 23671339
references.citation: Nature. 2012 Apr 11;485(7398):376-80
references.pmid: 22495300
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21081-6
references.pmid: 23204437
references.citation: Trends Neurosci. 1989 Oct;12(10):366-75
references.pmid: 2479133
references.citation: Mech Dev. 2002 Mar;112(1-2):157-60
references.pmid: 11850187
references.citation: Development. 1999 May;126(9):1903-16
references.pmid: 10101124
references.citation: Dev Biol. 2001 Dec 1;240(1):237-46
references.pmid: 11784059
references.citation: Dev Biol. 2007 Jun 15;306(2):703-13
references.pmid: 17493606
references.citation: Nucleic Acids Res. 2010 Aug;38(15):4985-97
references.pmid: 20385576
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9005-10
references.pmid: 12855770
references.citation: J Neurosci. 2010 Nov 24;30(47):16053-64
references.pmid: 21106844
references.citation: Neuron. 2011 Jun 9;70(5):939-50
references.pmid: 21658586
references.citation: J Comp Neurol. 2008 Jan 1;506(1):16-29
references.pmid: 17990269
references.citation: Nat Rev Neurosci. 2003 Apr;4(4):276-89
references.pmid: 12671644
references.citation: Nat Neurosci. 2010 Jun;13(6):700-7
references.pmid: 20473291
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17195-200
references.pmid: 21949399
references.citation: Cell. 1999 Jun 11;97(6):779-90
references.pmid: 10380929
references.citation: Prog Brain Res. 2007;160:111-33
references.pmid: 17499111
references.citation: PLoS Genet. 2011 Aug;7(8):e1002239
references.pmid: 21852962
references.citation: Mol Cell Biol. 2009 Jun;29(11):3045-61
references.pmid: 19332558
references.citation: Cell. 1999 Sep 3;98(5):585-95
references.pmid: 10490098
references.citation: Cell. 2014 Jan 16;156(1-2):195-207
references.pmid: 24439376
references.citation: Cell Rep. 2012 Aug 30;2(2):345-57
references.pmid: 22854024
references.citation: Eur J Neurosci. 2012 May;35(10):1573-85
references.pmid: 22607003
references.citation: J Comp Neurol. 1999 Oct 11;413(1):1-25
references.pmid: 10464367
references.citation: Annu Rev Neurosci. 1992;15:285-320
references.pmid: 1575444
references.citation: Nat Neurosci. 2007 Aug;10(8):963-9
references.pmid: 17618280
references.citation: Development. 2013 Aug;140(16):3297-302
references.pmid: 23900538
references.citation: Neuron. 2012 Jun 21;74(6):1075-86
references.pmid: 22726837
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3124-9
references.pmid: 10716726
references.citation: Brain Res. 1992 Oct 16;593(2):245-52
references.pmid: 1450931
references.citation: Nature. 2012 Aug 23;488(7412):517-21
references.pmid: 22842903
references.citation: Mol Biol Cell. 2014 Mar;25(5):633-42
references.pmid: 24371087
references.citation: J Neurosci. 2010 Feb 24;30(8):2824-34
references.pmid: 20181580
references.citation: Neuroscience. 1983 Dec;10(4):1185-201
references.pmid: 6320048
references.citation: Nat Genet. 2011 Jun 19;43(7):630-8
references.pmid: 21685913
references.citation: Development. 1999 Dec;126(23):5421-9
references.pmid: 10556066
references.citation: Neuron. 2000 Oct;28(1):91-101
references.pmid: 11086986
references.citation: Front Mol Neurosci. 2011 Dec 23;4:54
references.pmid: 22275881
references.citation: Trends Neurosci. 1990 Jul;13(7):266-71
references.pmid: 1695401
references.citation: J Neurosci. 1998 Aug 1;18(15):5723-45
references.pmid: 9671663
references.citation: J Mol Cell Biol. 2012 Dec;4(6):362-76
references.pmid: 22730554
references.citation: Cell. 2008 Jun 13;133(6):1093-105
references.pmid: 18555784
references.citation: J Histochem Cytochem. 1985 Feb;33(2):134-40
references.pmid: 2578498
references.citation: Nat Neurosci. 2003 Jun;6(6):557-63
references.pmid: 12754514
references.citation: Nat Neurosci. 2007 Sep;10(9):1151-9
references.pmid: 17721516
references.citation: J Neurosci. 2008 Mar 26;28(13):3291-7
references.pmid: 18367596
references.citation: Genes Dev. 2002 Aug 1;16(15):1890-905
references.pmid: 12154121
references.citation: Development. 2002 Feb;129(3):761-73
references.pmid: 11830575
references.citation: Genome Biol. 2008;9(9):R137
references.pmid: 18798982
references.citation: Neuron. 2013 Jun 5;78(5):839-54
references.pmid: 23684785
references.citation: Genes Dev. 2011 Sep 15;25(18):1982-96
references.pmid: 21937715
references.citation: J Neurosci. 2012 Oct 3;32(40):13729-43
references.pmid: 23035085
references.citation: Science. 2008 May 16;320(5878):946-9
references.pmid: 18487195
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14893-8
references.pmid: 20679223
references.citation: Science. 2007 Jun 8;316(5830):1497-502
references.pmid: 17540862
references.citation: Behav Brain Res. 2011 Aug 10;221(2):564-73
references.pmid: 20060022
references.citation: Cell. 2006 Apr 7;125(1):127-42
references.pmid: 16615895
references.citation: J Neurosci. 2010 Feb 24;30(8):2812-23
references.pmid: 20181579
references.citation: Development. 2011 Oct;138(19):4315-26
references.pmid: 21865321
references.citation: Cereb Cortex. 2003 Jun;13(6):661-9
references.pmid: 12764042
references.citation: Genes Dev. 2006 Dec 1;20(23):3199-214
references.pmid: 17158740
references.citation: Mol Cell. 2002 Jul;10(1):21-33
references.pmid: 12150904
references.citation: Nat Neurosci. 2005 Apr;8(4):451-7
references.pmid: 15778712
references.citation: Cereb Cortex. 2009 Jul;19 Suppl 1:i114-9
references.pmid: 19349379
references.citation: Development. 1999 Aug;126(15):3359-70
references.pmid: 10393115