Abstract
Agenesis of the corpus callosum (ACC) is a congenital abnormality of the brain structure. We have produced transgenic mice expressing both reverse tetracycline-controlled transactivator (rtTA) and transcriptional silencer (tTS) ubiquitously. Although the transgene products do not affect development of the mouse brain, one of the founder lines, TAS, showed ACC, suggesting transgenic disruption of endogenous gene(s). To identify the causative gene and its role in ACC, we performed pathological investigations of the brain and chromosomal mapping of foreign genes in TAS mice. Sixty-two percent of the heterozygous TAS mice showed ACC accompanied with formation of Probst bundles, as seen in human. Complete penetrance of ACC was observed in homozygous TAS mice. Furthermore, homozygous TAS fetuses revealed that ACC is a congenital anomaly. Moreover, axons of the corpus callosum were not repelled by the midline glial structures in TAS mice. These findings suggested that the causative gene for ACC is involved in critical steps in corpus callosum development. Multiple FISH analyses were performed to determine the site of transgene insertion. On 1-color FISH analyses, rtTA and tTS were detected on the A/B region of chromosome 18, suggesting cointegration of the transgenes. On 2-color FISH analyses, tTS signal was observed in a region from 9.3 to 16.9 Mb on chromosome 18. The TAS mice may serve as a useful model to identify a novel gene regulating corpus callosum development and to gain a new insight into molecular genetics of ACC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aboitiz F, Scheibel AB, Fisher RS, Zaidel E (1992) Fiber composition of the human corpus callosum. Brain Res 598:143–153
Andrews W, Liapi A, Plachez C, Camurri L, Zhang J et al (2006) Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain. Development 133:2243–2252
Bailey DW (1978) Source of subline divergence and their relative importance for sublines of six major inbred strains of mice. In: Morse HC III (ed) Origins of inbred mice. Academic Press, New York, pp 197–215
Barkovich AJ, Norman D (1998) Anomalies of the corpus callosum: correlation with further anomalies of the brain. AJR Am J Roentgenol 151:171–179
Blum A, Andre M, Droulle P, Husson S, Leheup B (1990) Prenatal echographic diagnosis of corpus callosum agenesis. The Nancy experience 1982–1989. Genet Couns 1:115–126
Briancon-Marjollet A, Ghogha A, Nawabi H, Triki I, Auziol C et al (2008) Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance. Mol Cell Biol 28:2314–2323
Bush JO, Soriano P (2009) Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Genes Dev 23:1586–1599
Chae T, Kwon YT, Bronson R, Dikkes P, Li E et al (1997) Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18:29–42
Cheng LE, Zhang J, Reed RR (2007) The transcription factor Zfp423/OAZ is required for cerebellar development and CNS midline patterning. Dev Biol 307:43–52
Donahoo AL, Richards LJ (2009) Understanding the mechanisms of callosal development through the use of transgenic mouse models. Semin Pediatr Neurol 16:127–142
Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J et al (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75:1417–1430
Fernandes M, Gutin G, Alcorn H, McConnell SK, Hebert JM (2007) Mutations in the BMP pathway in mice support the existence of two molecular classes of holoprosencephaly. Development 134:3789–3794
Gordon JW, Ruddle FH (1981) Integration and stable germ line transmission of genes injected into mouse pronuclei. Science 214:1244–1246
Gruber D, Waanders R, Collins RL, Wolfer DP, Lipp HP (1991) Weak or missing paw lateralization in a mouse strain (I/LnJ) with congenital absence of the corpus callosum. Behav Brain Res 46:9–16
Islam SM, Shinmyo Y, Okafuji T, Su Y, Naser IB et al (2009) Draxin, a repulsive guidance protein for spinal cord and forebrain commissures. Science 323:388–393
Janish R (1988) Transgenic animals. Science 240:1468–1474
Jeret JS, Serur D, Wisniewski K, Fisch C (1985–1986) Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatr Neurosci 12:101–103
Kadowaki M, Nakamura S, Machon O, Krauss S, Radice GL et al (2007) N-cadherin mediates cortical organization in the mouse brain. Dev Biol 304:22–33
LaMora A, Voigt MM (2009) Cranial sensory ganglia neurons require intrinsic N-cadherin function for guidance of afferent fibers to their final targets. Neuroscience 159:1175–1184
Livy DJ, Schalomon PM, Roy M, Zacharias MC, Pimenta J et al (1997) Increased axon number in the anterior commissure of mice lacking a corpus callosum. Exp Neurol 146:491–501
Loftus SK, Cannons JL, Incao A, Pak E, Chen A et al (2005) Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency. PLoS Genet 1:e38
Magara F, Müller U, Li ZW, Lipp HP, Weissmann C et al (1999) Genetic background changes the pattern of forebrain commissure defects in transgenic mice underexpressing the beta-amyloid-precursor protein. Proc Natl Acad Sci USA 96:4656–4661
Manhaes AC, Medina AE, Schmidt SL (2002) Sex differences in the incidence of tatal callosal agenesis in BALB/cCF mice. Neurosci Lett 325:159–162
Matsuda Y, Chapman VM (1995) Application of fluorescence in situ hybridization in genome analysis of the mouse. Electrophoresis 16:261–272
Matsuda Y, Nishida-Umehara C, Tarui H, Kuroiwa A, Yamada K et al (2005) Highly conserved linkage homology between birds and turtles: bird and turtle chromosomes are precise counterparts of each other. Chromosome Res 13:601–615
Meathrel K, Adamek T, Batt J, Rotin D, Doering LC (2002) Protein tyrosine phosphatase Sigma-deficient mice show aberrant cytoarchitecture and structural abnormalities in the central nervous system. J Neurosci Res 70:24–35
Meisler MH (1992) Insertional mutation of ‘classical’ and novel genes in transgenic mice. Trends Genet 8:341–344
Mendes SW, Henkemeyer M, Liebl DJ (2006) Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain. J Neurosci 26:882–892
Moes P, Schilmoeller K, Schilmoeller G (2009) Physical, motor, sensory and developmental features associated with agenesis of the corpus callosum. Child Care Health Dev 5:656–672
Parr BA, Shea MJ, Vassileva G, McMahon AP (1993) Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Development 119:247–261
Pilu G, Sandri F, Perolo A, Pittalis MC, Grisolia G et al (1993) Sonography of fetal agenesis of the corpus callosum: a survey of 35 cases. Ultrasound Obstet Gynecol 3:318–329
Potter M, Wax JS (1981) Genetics of susceptibility to pristane-induced plasmacytomas in BALB/cAn: reduced susceptibility in BALB/cJ with a brief description of pristane-induced arthritis. J Immunol 127:1591–1595
Radice GL, Rayburn H, Matsunami H, Knudsen KA, Takeichi M et al (1997) Developmental defects in mouse embryos lacking N-cadherin. Dev Biol 181:64–78
Raper JA (2000) Semaphorins and their receptors in vertebrates and invertebrates. Curr Opin Neurobiol 10:88–94
Ren T, Zhang J, Plachez C, Mori S, Richards LJ (2007) Diffusion tensor magnetic resonance imaging and tract-tracing analysis of Probst bundle structure in Netrin1-and DCC-deficient mice. J Neurosci 27:10345–10349
Richards LJ, Plachez C, Ren T (2004) Mechanisms regulating the development of the corpus callosum and its agenesis in mouse and human. Clin Genet 66:276–289
Roderick TH, Langley SH, Leiter EH (1985) Some unusual genetic characteristics of BALB/c and evidence for genetic variation among BALB/c substrains. Curr Top Microbiol Immunol 122:9–18
Serafini T, Colamarino SA, Leonardo ED, Wang H, Beddington R et al (1996) Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87:1001–1014
Shu T, Richards LJ (2001) Cortical axon guidance by the glial wedge during the development of the corpus callosum. J Neurosci 21:2749–2758
Shu T, Sundaresan V, McCarthy MM, Richards LJ (2003a) Slit2 guides both precrossing and postcrossing callosal axons at the midline in vivo. J Neurosci 23:8176–8184
Shu T, Puche AC, Richards LJ (2003b) Development of midline glial populations at the corticoseptal boundary. J Neurobiol 57:81–94
Valentino KL, Jones EG, Kane SA (1983) Expression of GFAP immunoreactivity during development of long fiber tracts in the rat CNS. Brain Res 285:317–336
Wahlsten D (1974) Heritable aspects of anomalous myelinated fiber tracts in the forebrain of the laboratory mouse. Brain Res 68:1–18
Wahlsten D (1977) Heredity and brain structure. In: Oliverio A (ed) Genetics, environment and intelligence. Elsevier, Amsterdam, pp 93–115
Wahlsten D (1982) Deficiency of corpus callosum varies with strain and supplier of the mice. Brain Res 239:329–347
Wahlsten D, Metten P, Crabbe JC (2003) Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+tf/tf has severely reduced hippocampal commissure and absent corpus callosum. Brain Res 971:47–54
Warming S, Liu P, Suzuki T, Akagi K, Lindtner S et al (2003) Evi3, a common retroviral integration site in murine B-cell lymphoma, encodes an EBFAZ-related Krüppel-like zinc finger protein. Blood 101:1934–1940
Woychik RP, Alagramam K (1988) Insertional mutagenesis in transgenic mice generated by the pronuclear microinjection procedure. Int J Dev Biol 42:1009–1017
Wu M, Hesse E, Morvan F, Zhang JP, Correa D et al (2009) Zfp521 antagonizes Runx2, delays osteoblast differentiation in vitro, and promotes bone formation in vivo. Bone 44:528–536
Yoshida M, Suda Y, Matsuo I, Miyamoto N, Takeda N et al (1997) Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124:101–111
Acknowledgments
This study was supported by a grant (No. 21650086) from the Ministry of Education, Science, Sports, and Culture of Japan to FS. The authors thank the staff of the Laboratory Animal Resource Center, University of Tsukuba, for their excellent technical maintenance of TAS mice.
Author information
Authors and Affiliations
Corresponding author
Additional information
S. Mizuno, A. Mizobuchi, and H. Iseki contributed equally to this work.
Electronic supplementary material
Expression of transgenes in transgenic mouse line 162. The tTS transgene was constitutively expressed in the cerebrum (lane 1), thymus (lane 3), lung (lane 4), liver (lane 6), kidney (lane 7), spleen (lane 8), small intestine (lane 9), and skeletal muscle (lane 10). The rtTA transgene was strongly expressed in the cerebrum and skeletal muscle. Weak expression of rtTA was observed in the thymus, lung, liver, kidney, spleen, and small intestine
Rights and permissions
About this article
Cite this article
Mizuno, S., Mizobuchi, A., Iseki, H. et al. A novel locus on proximal chromosome 18 associated with agenesis of the corpus callosum in mice. Mamm Genome 21, 525–533 (2010). https://doi.org/10.1007/s00335-010-9292-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-010-9292-4