title: Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi.
abstract: Disrupted-in-Schizophrenia 1 (DISC1) is a promising genetic risk factor for major mental disorders. Many groups repeatedly reported a role for DISC1 in brain development in various strains of mice and rats by using RNA interference (RNAi) approach. Nonetheless, due to the complexity of its molecular disposition, such as many splice variants and a spontaneous deletion in a coding exon of the DISC1 gene in some mouse strains, there have been debates on the interpretation on these published data. Thus, in this study, we address this question by DISC1 knockdown via short-hairpin RNAs (shRNAs) against several distinct target sequences with more than one delivery methodologies into several mouse strains, including C57BL/6, ICR, and 129X1/SvJ. Here, we show that DISC1 knockdown by in utero electroporation of shRNA against exons 2, 6, and 10 consistently results in neuronal migration defects in the developing cerebral cortex, which are successfully rescued by co-expression of full-length DISC1. Furthermore, lentivirus-mediated shRNA also led to migration defects, which is consistent with two other methodologies already published, such as plasmid-mediated and retrovirus-mediated ones. The previous study by Song's group also reported that, in the adult hippocampus, the phenotype elicited by DISC1 knockdown with shRNA targeting exon 2 was consistently seen in both C57BL/6 and 129S6 mice. Taken together, we propose that some of DISC1 isoforms that are feasible to be knocked down by shRNAs to exon 2, 6, and 10 of the DISC1 gene play a key role for neuronal migration commonly in various mouse strains and rats.
authors.affiliation: Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Kubo
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomita
authors.forename: Asuka
authors.initials: A
authors.lastname: Uto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuroda
authors.forename: Saurav
authors.initials: S
authors.lastname: Seshadri
authors.forename: Jared
authors.initials: J
authors.lastname: Cohen
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology*; D018274:Electroporation / Q000379:methods; D005260:Female; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D016086:Lentivirus; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D014599:Uterus
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins
references.citation: Nat Cell Biol. 2006 Jan;8(1):17-26
references.pmid: 16341208
references.citation: Nat Neurosci. 2010 Mar;13(3):327-32
references.pmid: 20139976
references.citation: J Neurosci. 2009 Oct 14;29(41):12768-75
references.pmid: 19828788
references.citation: Mol Psychiatry. 2007 Oct;12(10):897-9
references.pmid: 17895924
references.citation: Neuron. 2009 Sep 24;63(6):761-73
references.pmid: 19778506
references.citation: Science. 2002 Apr 19;296(5567):550-3
references.pmid: 11910072
references.citation: Schizophr Bull. 2006 Jul;32(3):409-16
references.pmid: 16699061
references.citation: Cereb Cortex. 2009 Jul;19 Suppl 1:i120-5
references.pmid: 19395528
references.citation: Genes Dev. 2006 Jun 1;20(11):1511-24
references.pmid: 16705040
references.citation: Nat Cell Biol. 2005 Dec;7(12):1167-78
references.pmid: 16299498
references.citation: Gene. 1991 Dec 15;108(2):193-9
references.pmid: 1660837
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8196-201
references.pmid: 9223338
references.citation: Neuron. 2009 Sep 24;63(6):774-87
references.pmid: 19778507
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7
references.pmid: 16484369
references.citation: Arch Gen Psychiatry. 2008 Sep;65(9):996-1006
references.pmid: 18762586
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15873-8
references.pmid: 19805229
references.citation: Annu Rev Neurosci. 2003;26:441-83
references.pmid: 12626695
references.citation: J Neurosci. 2010 Aug 4;30(31):10431-40
references.pmid: 20685985
references.citation: Cell. 2007 Sep 21;130(6):1146-58
references.pmid: 17825401
references.citation: J Neurosci. 2007 Jan 3;27(1):15-26
references.pmid: 17202468
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7076-81
references.pmid: 18458327
references.citation: Neuron. 2010 Jul 15;67(1):33-48
references.pmid: 20624590
references.citation: Prog Brain Res. 2009;179:9-15
references.pmid: 20302813
references.citation: Genetics. 2006 Aug;173(4):2407-10
references.pmid: 16751659
references.citation: Neuron. 2007 May 3;54(3):387-402
references.pmid: 17481393
references.citation: Neuron. 2010 Feb 25;65(4):480-9
references.pmid: 20188653
references.citation: Cell. 2009 Mar 20;136(6):1017-31
references.pmid: 19303846
references.citation: J Neurosci. 2003 Nov 5;23(31):9996-10001
references.pmid: 14602813
references.citation: Neuroscience. 2001;103(4):865-72
references.pmid: 11301197
references.citation: Trends Neurosci. 2009 Sep;32(9):485-95
references.pmid: 19712980
references.citation: Hum Mol Genet. 2009 Sep 1;18(17):3286-97
references.pmid: 19502360
references.citation: Biol Psychiatry. 2006 Jun 15;59(12):1189-97
references.pmid: 16797264