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Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene

Nature Genetics volume 13, pages 275–283 (1996)Cite this article

Abstract

The paired-class homeobox–containing gene, Cartl, is expressed in forebrain mesenchyme, branchial arches, limb buds and cartilages during embryogenesis. Here, we show that Cart1–homozygous mutant mice are born alive with acrania and meroanencephaly but die soon after birth — a phenotype that strikingly resembles a corresponding human syndrome caused by a neural tube closure defect. Developmental studies suggest that Cart1 is required for forebrain mesenchyme survival and that its absence disrupts cranial neural tube morphogenesis by blocking the initiation of closure in the midbrain region that ultimately leads to the generation of lethal craniofacial defects. Prenatal treatment of Cart1 homozygous mutants with folic acid suppresses the development of the acrania/meroanencephaly phenotype.

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References

  1. Edmonds, L.D. & James, L.M. Temporal trends in the prevalence of congenital malformations at birth based on the Birth Defects Monitoring Program, United States, 1979–1987. MMWR 39, 19–23 (1990).

    CAS  PubMed  Google Scholar 

  2. Copp, A.J., Brook, F.A., Estibeiro, J.P., Shum, A.S. & Cockroft, D.L. The embryonic development of mammalian neural tube defects. Prog. Neurobiol. 35, 363–403 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Hunter, A.G.W. Brain and spinal cord. in Human Malformations and Related Anomalies (eds Stevenson, R. E., Hall, J.G. & Goodman, R.M.) 109–137 (Oxford University Press, Oxford, 1993).

    Google Scholar 

  4. Campbell, L.R., Dayton, D.H. & Sohal, G.S. Neural tube defects: a review of human and animal studies on the etiology of neural tube defects. Teratology 34, 171–187 (1986).

    Article  CAS  PubMed  Google Scholar 

  5. Morriss-Kay, G.M. Growth and development of pattern in the cranial neural epithelium of rat embryos during neurulation. J. Embryol. Exp. Morph. 65 (Suppl), 225–241 (1981).

    PubMed  Google Scholar 

  6. Geelen, J.A.G. & Langman, J. Closure of the neural tube in the cephalic region of the mouse embryo. Anat. Rec. 189, 625–640 (1977).

    Article  CAS  PubMed  Google Scholar 

  7. Sakai, Y. Neurulation in the mouse: manner and timing of neural tube closure. Anat. Rec. 223, 194–203 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Juriloff, D.M., Harris, M.J., Tom, C. & Macdonald, K.B. Normal mouse strains differ in the site of initiation of closure of the cranial neural tube. Teratology 44, 225–233 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Schoenwolf, G.C. & Smith, J.L. Mechanisms of neurulation: traditional viewpoint and recent advances. Development 109, 243–270 (1990).

    CAS  PubMed  Google Scholar 

  10. Chen, Z.F. & Behringer, R.R. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Zhao, G.Q., Eberspaecher, H., Seldin, M.F. & deCrombrugghe, B. The gene for the homeodomain-containing protein Cart-1 is expressed in cells that have a chondrogenic potential during embryonic development. Mech. Dev. 48, 245–254 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Zhao, G.-Q., Zhou, X., Eberspaecher, H., Solursh, M. & deCrombrugghe, B. Cartilage homeoprotein 1, a homeoprotein selectively expressed in chondrocytes. Proc. Natl. Acad. Sci. USA 90, 8633–8637 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rudnick, A., Ling, T.Y., Odagiri, H., Rutter, W.J. & German, M.S. Pancreatic beta cells express a diverse set of homeobox genes. Proc. Natl. Acad. Sci. USA 91, 12203–12207 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Noden, D.M. Interactions and fates of avian craniofacial mesenchyme. Development 103, 121–140 (1988).

    PubMed  Google Scholar 

  15. Le Douarin, N.M., Ziller, C. & Couly, G. Patterns of neural crest derivatives in the avian embryos: In vivo and in vitro studies. Dev. Biol. 159, 24–49 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Noden, D.M. The role of the neural crest in patterning of avian cranial skeletal, connective, and muscle tissues. Dev. Biol. 96, 144–165 (1983).

    Article  CAS  PubMed  Google Scholar 

  17. Graham, A., Heyman, I. & Lumsden, A. Even-numbered rhombomeres control the apoptotic elimination of neural crest cells from odd-numbered rhombomeres in the chick hindbrain. Development 119, 233–245 (1993).

    CAS  PubMed  Google Scholar 

  18. Smithells, R.W. et al. Prevention of neural tube defect recurrences in Yorkshire: final report. Lancet 2, 498–499 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Le Douarin, N.M. The Neural Crest. (Cambridge University Press, London, 1982).

    Google Scholar 

  20. Couly, G.F., Coltey, P.M. & Le Douarin, N.M. The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 117, 409–429 (1993).

    CAS  PubMed  Google Scholar 

  21. Cheyette, B.N., Green, P.J., Martin, K., Garren, H., Hartenstein, V. & Zipursky, S.L. The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12, 977–996 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Xiong, W.C. & Montell, C. Defective glia induce neuronal apoptosis in the repo visual system Wrosophila. Neuron 14, 581–590 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Wolf, C., Thisse, C., Stoetzel, C., Thisse, B., Gerlinger, P. & Perrin-Schmitt, F. The M-twist gene of Mus is expressed in subsets of mesodermal cells and is closely related to the Xenopus X-twi and Drosophila twist genes. Dev.Biol. 143, 363–373 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Mitchell, P.J., Timmons, P.M., Hebert, J.M., Rigby, P.W.J. & Tjian, R. Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes Dev. 5, 105–119 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Morriss, G.M. & Solursh, M. The role of primary mesenchyme in normal and abnormal morphogenesis of mammalian neural folds. Zoon 6, 33–38 (1978).

    Google Scholar 

  26. Morriss, G.M. & Solursh, M. Regional differences in mesenchymal cell morphology and glycosaminoglycans in early neural fold stage rat embryos. J. Embryol. Exp. Morphol. 46, 37–52 (1978).

    CAS  PubMed  Google Scholar 

  27. Gordon, R.A. A review of the theories of vertebrate neurulation and their relationship to the mechanics of neural tube birth defects. J. Embryol. Exp. Morphol. 89, 229–255 (1985).

    PubMed  Google Scholar 

  28. Morris-Wiman, J. & Brinkley, L.L. Changes in mesenchymal cell and hyaluronate distribution correlate with in vivo elongation of the mouse mesencephalic neural folds. Anat. Rec. 226, 383–395 (1990).

    Article  CAS  PubMed  Google Scholar 

  29. Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Mansour, S.L., Thomas, K.R. & Capecchi, M.R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature 336, 348–352 (1988).

    Article  CAS  PubMed  Google Scholar 

  31. McMahon, A.P. & Bradley, A., The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62, 1073–1085 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. Bradley, A. Production and analysis of chimeric mice. in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (ed Robertson, E.J.), 113–151 (IRL Press, Oxford, 1987).

    Google Scholar 

  33. Kochhar, D.M. Limb development in mouse embryos I. Analysis of teratogenic effects of retinoic acid. Teratology 7, 289–298 (1973).

    Article  CAS  PubMed  Google Scholar 

  34. Ojeda, J.L., Barbosa, E. & Bosque, P.G. Selective skeletal staining in whole chicken embryos: a rapid alcian blue technique. Stain Technol. 45, 137–138 (1970).

    Article  CAS  PubMed  Google Scholar 

  35. Kaufman, M.H. Morphological stages of postimplantation embryonic development. in Postimplantation Mammalian Embryos, A Practical Approach (eds Copp, A J. & Cockroft, D.L.) 81–91 (IRL Press, Oxford, 1990).

    Google Scholar 

  36. Wilkinson, D.G., Bailes, J.A., Champion, J.E. & McMahon, A.P. A molecular analysis of mouse development from 8 to 10 days post coitum detects changes only in embryonic globin expression. Development 99, 493–500 (1987).

    CAS  PubMed  Google Scholar 

  37. Sassoon, D.A., Garner, I. & Buckingham, M. Transcripts of a-cardiac and a-skeletal actins are early markers for myogenesis in the mouse embryo. Development 104, 155–164 (1988).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas, 77030, USA

    Qi Zhao, Richard R. Behringer & Benoit de Crombrugghe

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  1. Qi Zhao
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  2. Richard R. Behringer
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  3. Benoit de Crombrugghe
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Zhao, Q., Behringer, R. & de Crombrugghe, B. Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene. Nat Genet 13, 275–283 (1996). https://doi.org/10.1038/ng0796-275

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