title: Truncated Cables1 causes agenesis of the corpus callosum in mice.
abstract: Agenesis of the corpus callosum (ACC) is a congenital abnormality of the brain structure. More than 60 genes are known to be involved in corpus callosum development. However, the molecular mechanisms underlying ACC are not fully understood. Previously, we produced a novel transgenic mouse strain, TAS, carrying genes of the tetracycline-inducible expression system that are not involved in brain development, and inherited ACC was observed in the brains of all homozygous TAS mice. Although ACC was probably induced by transgene insertion mutation, the causative gene and the molecular mechanism of its pathogenesis remain unclear. Here, we first performed interphase three-color fluorescence in situ hybridization (FISH) analysis to determine the genomic insertion site. Transgenes were inserted into chromosome 18 ∼12.0 Mb from the centromere. Gene expression analysis and genomic PCR walking showed that the genomic region containing exon 4 of Cables1 was deleted by transgene insertion and the other exons of Cables1 were intact. The mutant allele was designated as Cables1(TAS). Interestingly, Cables1(TAS) mRNA consisted of exons 1-3 of Cables1 and part of the transgene that encoded a novel truncated Cables1 protein. Homozygous TAS mice exhibited mRNA expression of Cables1(TAS) in the fetal cerebrum, but not that of wild-type Cables1. To investigate whether a dominant negative effect of Cables1(TAS) or complete loss of function of Cables1 gives rise to ACC, we produced Cables1-null mutant mice. ACC was not observed in Cables1-null mutant mice, suggesting that a dominant negative effect of Cables1(TAS) impairs callosal formation. Moreover, ACC frequency in Cables1(+/TAS) mice was significantly lower than that in Cables1(-/TAS) mice, indicating that wild-type Cables1 interfered with the dominant negative effect of Cables1(TAS). This study indicated that truncated Cables1 causes ACC and wild-type Cables1 contributes to callosal formation.
authors: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan.
authors: Seiya
authors: S
authors: Mizuno
authors: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan.
authors: Dinh T H
authors: DT
authors: Tra
authors: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan.
authors: Atsushi
authors: A
authors: Mizobuchi
authors: 1] Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan [2] Project Research Division, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
authors: Hiroyoshi
authors: H
authors: Iseki
authors: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan.
authors: Saori
authors: S
authors: Mizuno-Iijima
authors: Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors: Jun-Dal
authors: JD
authors: Kim
authors: Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors: Junji
authors: J
authors: Ishida
authors: Laboratory of Animal Genetics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
authors: Yoichi
authors: Y
authors: Matsuda
authors: Center for Experimental Medicine, Jichi Medical University, Shimotsuke, Japan.
authors: Satoshi
authors: S
authors: Kunita
authors: Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors: Akiyoshi
authors: A
authors: Fukamizu
authors: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan.
authors: Fumihiro
authors: F
authors: Sugiyama
authors: Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Japan.
authors: Ken-ichi
authors: K
authors: Yagami
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D016213:Cyclins / Q000172:deficiency* / Q000235:genetics*; D005091:Exons; D056726:Genetic Association Studies; D006720:Homozygote; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C411580:Cables1 protein, mouse; D002352:Carrier Proteins; D016213:Cyclins; D010750:Phosphoproteins; D012333:RNA, Messenger