A novel locus on proximal chromosome 18 associated with agenesis of the corpus callosum in mice

Mammalian Genome volume 21, pages525–533(2010)Cite this article

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, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Aboitiz F, Scheibel AB, Fisher RS, Zaidel E (1992) Fiber composition of the human corpus callosum. Brain Res 598:143–153

    CAS  Article  PubMed  Google Scholar 

  2. 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

    CAS  Article  PubMed  Google Scholar 

  3. 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

    Google Scholar 

  4. Barkovich AJ, Norman D (1998) Anomalies of the corpus callosum: correlation with further anomalies of the brain. AJR Am J Roentgenol 151:171–179

    Google Scholar 

  5. 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

    CAS  PubMed  Google Scholar 

  6. 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

    CAS  Article  PubMed  Google Scholar 

  7. Bush JO, Soriano P (2009) Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Genes Dev 23:1586–1599

    CAS  Article  PubMed  Google Scholar 

  8. 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

    CAS  Article  PubMed  Google Scholar 

  9. 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

    CAS  Article  PubMed  Google Scholar 

  10. Donahoo AL, Richards LJ (2009) Understanding the mechanisms of callosal development through the use of transgenic mouse models. Semin Pediatr Neurol 16:127–142

    Article  PubMed  Google Scholar 

  11. 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

    CAS  Article  PubMed  Google Scholar 

  12. 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

    CAS  Article  PubMed  Google Scholar 

  13. Gordon JW, Ruddle FH (1981) Integration and stable germ line transmission of genes injected into mouse pronuclei. Science 214:1244–1246

    CAS  Article  PubMed  Google Scholar 

  14. 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

    CAS  Article  PubMed  Google Scholar 

  15. 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

    CAS  Article  PubMed  Google Scholar 

  16. Janish R (1988) Transgenic animals. Science 240:1468–1474

    Article  Google Scholar 

  17. 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

    Google Scholar 

  18. 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

    CAS  Article  PubMed  Google Scholar 

  19. 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

    CAS  Article  PubMed  Google Scholar 

  20. 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

    CAS  Article  PubMed  Google Scholar 

  21. 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

    Article  PubMed  Google Scholar 

  22. 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

    CAS  Article  PubMed  Google Scholar 

  23. 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

    CAS  Article  PubMed  Google Scholar 

  24. Matsuda Y, Chapman VM (1995) Application of fluorescence in situ hybridization in genome analysis of the mouse. Electrophoresis 16:261–272

    CAS  Article  PubMed  Google Scholar 

  25. 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

    CAS  Article  PubMed  Google Scholar 

  26. 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

    CAS  Article  PubMed  Google Scholar 

  27. Meisler MH (1992) Insertional mutation of ‘classical’ and novel genes in transgenic mice. Trends Genet 8:341–344

    CAS  PubMed  Google Scholar 

  28. 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

    CAS  Article  PubMed  Google Scholar 

  29. 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

    Article  Google Scholar 

  30. 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

    CAS  PubMed  Google Scholar 

  31. 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

    CAS  Article  PubMed  Google Scholar 

  32. 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

    CAS  PubMed  Google Scholar 

  33. 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

    CAS  Article  PubMed  Google Scholar 

  34. Raper JA (2000) Semaphorins and their receptors in vertebrates and invertebrates. Curr Opin Neurobiol 10:88–94

    CAS  Article  PubMed  Google Scholar 

  35. 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

    CAS  Article  PubMed  Google Scholar 

  36. 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

    CAS  Article  PubMed  Google Scholar 

  37. 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

    CAS  PubMed  Google Scholar 

  38. 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

    CAS  Article  PubMed  Google Scholar 

  39. Shu T, Richards LJ (2001) Cortical axon guidance by the glial wedge during the development of the corpus callosum. J Neurosci 21:2749–2758

    CAS  PubMed  Google Scholar 

  40. 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

    CAS  PubMed  Google Scholar 

  41. Shu T, Puche AC, Richards LJ (2003b) Development of midline glial populations at the corticoseptal boundary. J Neurobiol 57:81–94

    Article  PubMed  Google Scholar 

  42. 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

    CAS  PubMed  Google Scholar 

  43. Wahlsten D (1974) Heritable aspects of anomalous myelinated fiber tracts in the forebrain of the laboratory mouse. Brain Res 68:1–18

    CAS  Article  PubMed  Google Scholar 

  44. Wahlsten D (1977) Heredity and brain structure. In: Oliverio A (ed) Genetics, environment and intelligence. Elsevier, Amsterdam, pp 93–115

    Google Scholar 

  45. Wahlsten D (1982) Deficiency of corpus callosum varies with strain and supplier of the mice. Brain Res 239:329–347

    CAS  Article  PubMed  Google Scholar 

  46. 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

    CAS  Article  PubMed  Google Scholar 

  47. 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

    CAS  Article  PubMed  Google Scholar 

  48. Woychik RP, Alagramam K (1988) Insertional mutagenesis in transgenic mice generated by the pronuclear microinjection procedure. Int J Dev Biol 42:1009–1017

    Google Scholar 

  49. 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

    CAS  Article  PubMed  Google Scholar 

  50. 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

    CAS  PubMed  Google Scholar 

Download references

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

Author notes

  1. Hiroyoshi Iseki

    Present address: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka City, Saitama, 350-1241, Japan

Affiliations

  1. Laboratory Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Seiya Mizuno, Atsushi Mizobuchi, Hiroyoshi Iseki, Saori Iijima, Satoshi Kunita, Fumihiro Sugiyama & Ken-ichi Yagami

  2. Laboratory of Animal Genetics, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan

    Yoichi Matsuda

Authors
  1. Seiya Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsushi Mizobuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyoshi Iseki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Saori Iijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoichi Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Kunita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fumihiro Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ken-ichi Yagami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fumihiro Sugiyama.

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

Supplementary material 1 (PDF 44 kb)

Rights and permissions

Reprints 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

Download citation

Keywords

  • Corpus Callosum
  • Commissural Axon
  • Complete Penetrance
  • Rostral Forebrain
  • Callosal Defect