Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain

Abstract

The expression of the FMR–1 gene, which is implicated in fragile–X syndrome was investigated in human fetuses by in situ hybridization. In 8 and 9 week–old fetuses, FMR–1 mRNAs are expressed in proliferating and migrating cells of the nervous system, in the retina, and in several non–nervous tissues. In the brain of 25 week–old fetuses, FMR–1 mRNAs are produced in all nearly differenciated structures, with the highest level in cholinergic neurons of the nucleus basalis magnocellularis and in pyramidal neurons of hippocampus. The early transcription of FMR–1 gene and the distribution of FMR–1 mRNAs in human fetuses suggest that alterations of FMR–1 gene expression may contribute to the pathogenesis of fragile–X syndrome and especially the mental retardation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Webb, T. In The fragile X syndrome, (ed. Davies, K.E.) 40–55 (Oxford University Press, Oxford, 1989).

    Google Scholar 

  2. Hagerman, R.J. In Fragile X syndrome, (ed. Hagerman, R.J. and Cronister-Sliverman, A.) 3–68 (The John Hopkins University Press, London, 1991).

    Google Scholar 

  3. Cohen, I.L. et al. Why are autism and the fragile X syndrome associated? Conceptual and methodological issues. Am. J. hum. Genet. 48, 195–202 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wisniewski, K.E., Segan, S.M., Miezejeski, C.M., Sersen, E.A. & Rudelli, R.D. The fragile X syndrome: Neurological, electrophysiological, and neuropathological abnormalities. Am. J. med. Genet. 38, 476–480 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Loesch, D.Z. et al. Fragile-X family with unusual digital and facial abnormalities, cleft lip and palate, and epilepsy. Am. J. med. Genet. 44, 543–550 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Oberlé, I. et al. Instability of a 550–base pair-DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1087–1102 (1991).

    Article  Google Scholar 

  7. Kremer, E.J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711–1714 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Yu, S. et al. Fragile X genotype characterized by an unstable region of DNA. Science 252, 1179–1181 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Verkerk, A.J. et al. Identification of a gene FMR1 containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 55, 905–914 (1991).

    Article  Google Scholar 

  10. Fu, Y.H. et al. Variation of the CGG repeat at the fragile X site. Results in genetic instability: Resolution of the Sherman Paradox. Cell 67, 1047–1058 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Yu, S. et al. Fragile X syndrome: Unique genetics of the heritable unstable elements. Am. J. hum. Genet. 50, 968–990 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Rousseau, F. et al. Efficient and reliable direct DNA-based diagnosis of the fragile-X mental retardation syndrome. New Engl. J. Med. 325, 1673–1681 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Bell, M.V. et al. Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome. Cell 64, 861–866 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Rousseau, F. et al. Four chromosomal breakpoints and four new probes mark out a 10 cM region encompassing the FRAXA locus. Am. J. hum. Genet. 48, 108–116 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hansen, R.S., Gartler, S.M., Scott, C.R., Chen, S.H. & Laird, C.D. Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum. molec. Genet. 1, 571–578 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Vincent, A. et al. Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis. Nature 349, 624–626 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Mandel, J.L. et al. Conference report: Fifth International Workshop on the fragile-X and X-linked mental retardation. Am. J. med. Genet. 43, 5–20 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Devys, D. et al. Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am. J. med. Genet. 43, 208–216 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Wöhrle, D., Hirst, M.C., Kennerknecht, I., Davies, K.E. & Steinbach, P. Genotype mosaicism in fragile X fetal tissues. Hum. Genet. 89, 114–116 (1992).

    Article  PubMed  Google Scholar 

  21. Heitz, D. et al. Isolation of sequences that span the Fragile X and identification of a fragile X-related CpG island. Science 251, 1736–1739. (1991).

    Article  Google Scholar 

  22. Gedeon, A.K. et al. Fragile X syndrome without CCG amplification has an FMR1 deletion. Nature Genet. 1, 341–344 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Wöhrle, D. et al. A microdeletion of less than 250kb, including the proximal part of the FMR-1 gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome. Am. J. hum. Genet. 51, 298–306 (1992).

    Google Scholar 

  24. De Boulle, K. et al. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nature Genet. 3, 31–35 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Hanzlik, A.J., Osemlak, M.M., Hauser, M.A. & Kurnit, D.M. A recombination-based assay demonstrates that the fragile X sequence is transcribed widely during development. Nature Genet. 3, 44–48 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Hinds, H.L. et al. Tissue specific expression of FMR1 provides evidences for a functional role in Fragile-X syndrome. Nature Genet. 3, 36–43 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Nowakowski, R.S. In Fetal neural development and adult schizophrenia. (eds Mednick, S.A. et al.) 69–96 (Cambridge University Press, Cambridge, 1991).

    Google Scholar 

  28. Barkovich, A.J., Gressens, P. & Evrard, P., Formation, maturation, and disorders of brain neocortex. Am. J. Neuroradiol. 13, 423–446 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Rudelli, R.D., Brown, W.T. & Wisniewski, H.M. Adult fragile X syndrome. Acta neuropathol. (Berl.) 67, 289–295 (1985).

    Article  CAS  Google Scholar 

  30. Bauman, M. & Kemper, T.L. Histoanatomic observations of the brain in early infantile autism. Neurology 35, 866–874 (1985).

    Article  CAS  PubMed  Google Scholar 

  31. Meencke, H.J. & Janz, D. Neuropathological findings in primary generalized epilepsy: A study of eight cases. Epilepsia 25, 8–21 (1984).

    Article  CAS  PubMed  Google Scholar 

  32. Chugani, H.T. et al. Infantile spasms: I. PET identifies focal cortical dysgenesis in cryptogenic cases for surgical treatment. Ann. Neurol. 27, 406–413 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Palmini, A. et al. Neuronal migration disorders: A contribution of modern neuroimaging to the etiologic diagnosis of epilepsy. Can. J. neurol. Sci. 18, 580–587 (1991).

    Article  CAS  PubMed  Google Scholar 

  34. Palmini, A. et al. Focal neuronal migration disorders and intractable partial epilepsy: A study of 30 patients. Ann. Neurol. 30, 741–749 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. Palmini, A., Andermann, F., Olivier, A., Tampieri, D., Robitaille, Y. Neuronal migration disorders and intractable partial epilepsy: results of surgical treatment. Ann. Neurol. 30, 750–757 (1991).

    Article  CAS  PubMed  Google Scholar 

  36. Gillberg, C., Persson, E. & Wahlstrom, J. The autism-fragile X syndrome (AFRAX): A population based study often boys. J. ment. Defic. Res. 30, 27–39 (1986).

    PubMed  Google Scholar 

  37. Hagerman, R.J., Jackson, A.W., Levitas, A., Rimland, B. & Braden, M. An analysis of autism in 50 males with the fragile X syndrome. Am. J. med. Genet. 23, 359ndash;370 (1986).

    Article  CAS  PubMed  Google Scholar 

  38. Bergonzi, P., Ferri, R., Elia, M. & Musumeci, S.A. Epileptic seizures and fra(X) syndrome. Am. J. med. Genet. 38, 510 (1991).

    Article  CAS  PubMed  Google Scholar 

  39. Musumeci, S.A. et al. Epilepsy and fragile X syndrome: a follow-up study. Am. J. med. Genet. 38, 511–513 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Malmgren, H. et al. Infantile autism-Fragile X: Molecular findings support genetic heterogeneity. Am. J. med. Genet. 44, 830–833 (1992).

    Article  CAS  PubMed  Google Scholar 

  41. Mesulam, M.M., Mufson, E.J., Levey, A.I. & Wainer, B.H. Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei basalis (substantia innominata) and hypothalamus in the rhesus monkey. J. comp. Neurol. 214, 170–197 (1983).

    Article  CAS  PubMed  Google Scholar 

  42. Mesulam, M.M., Mufson, E.J., Wainer, B.H. & Levey, A.I. Central cholinergic pathways in the rat: An overview based on an alternative nomenclature (Chl-Ch6). Neurosci. 10, 1185–1201 (1983).

    Article  CAS  Google Scholar 

  43. Johnston, M.V., McKinney, M. & Coyle, J.T. Evidence for a cholinergic projection to neocortex from neurons in basal forebrain. Proc. natn. Acad. Sci. U.S.A. 76, 5392–5396 (1979).

    Article  CAS  Google Scholar 

  44. Mufson, E.J., Kehr, A., Wainer, B.H. & Mesulam, M.M. Cortical effects of neurotoxic damage to the nucleus basalis in rats: Persistent loss of extrinsic cholinergic input and lack of transsynaptic effect upon the number of somatostatin-containing, cholinesterase-positive and cholinergic cortical neurons. Brain Res. 417, 385–388, (1987).

    Article  CAS  PubMed  Google Scholar 

  45. Freund, L.S. & Reiss, A.L. Cognitive profiles associated with the fra(X) syndrome in males and females. Am. J. med. Genet. 38, 542–547 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Cianchetti, C. et al. Neuropsychological, psychiatric, and physical manifestations in 149 members from 18 Fragile X families. Am. J. med. Genet. 40, 234–243 (1991).

    Article  CAS  PubMed  Google Scholar 

  47. Von Flindt (de), R., Bybel, B., Chudley, A.E. & Lopez, F. Short term memory and cognitive variability in adult Fragile X females. Am. J. med. Genet. 38, 488–492 (1991).

    Article  Google Scholar 

  48. McConnell, S.K. The generation of neuronal diversity in the central nervous system. Ann. Rev. Neurosci. 14, 296–300 (1991).

    Article  Google Scholar 

  49. Reiss, A.L., Aylward, E., Freund, L.S., Joshi, P.K., and Bryan, R.N. Neuroanatomy of fragile X syndrome: The posterior fossa. Ann. Neurol. 29, 26–32 (1991).

    Article  CAS  PubMed  Google Scholar 

  50. Dunn, H.G. et al. Mental retardation as a sex-linked defect. Am. J. ment. Defic. 67, 827–848 (1963).

    Google Scholar 

  51. Desai, H.B., Donat, J., Shokeir, M.H.K. & Munoz, D.G. Amyotrophic lateral sclerosis in a patient with fragile X syndrome. Neurology 40, 378–380 (1990).

    Article  CAS  PubMed  Google Scholar 

  52. Arinami, J., Sato, M., Nakajima, S. & Kondo, I. Auditory brain-stem responses in the fragile X syndrome. Am. J. hum. Genet. 43, 46–51 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ferri, R. et al. In Evoked Potentials. III: The Third International Evoked Potentials Symposium (eds Barber, C. & Blum, T.) 167–169 (Butterworths, Boston, 1988).

    Google Scholar 

  54. Bloch, B.T. et al. In situ hybridization histochemistry for the analysis of gene expression in the endocrine and central nervous system tissue: A 3-year experience. J. Neurosci. Res. 16, 183–200 (1988).

    Article  Google Scholar 

  55. Berod, A., Biguet, N.F., Dumas, S., Bloch, B. and Mallet, J. Modulation of tyrosine hydroxylase gene expression in the central nervous system visualized by in situ hybridization. Proc. natn. Acad. Sci. U.S.A. 84, 1699–1703 (1987).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abitbol, M., Menini, C., Delezoide, AL. et al. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain. Nat Genet 4, 147–153 (1993). https://doi.org/10.1038/ng0693-147

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0693-147

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing