Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi.
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.
Kubo
Ken-Ichiro
K
Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
Tomita
Kenji
K
Uto
Asuka
A
Kuroda
Keisuke
K
Seshadri
Saurav
S
Cohen
Jared
J
Kaibuchi
Kozo
K
Kamiya
Atsushi
A
Nakajima
Kazunori
K
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
C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins
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