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:

Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse

Abstract

During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.

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

Figure 1: Targeted inactivation of Hesx1.
Figure 2: Histological analysis of the Hesx1 mutants.
Figure 3: Whole-mount analysis of anterior neural markers in Hesx1 mutant (a,c,e,g,i,j) and wild-type (b,d,f,h,k) embryos.
Figure 4: Predicted open reading frame of human HESX1 compared with the mouse Hesx1 and Xenopus XANF1 proteins.
Figure 5: Mapping of HESX1. Fluorescent in situ hybridization of HESX1 on normal male metaphase chromosomes showing hybridization to 3p21 (arrows).
Figure 6: Detection of a homozygous missense mutation in HESX1 of the probands IV.4 and IV.5.
Figure 7: Electromobility shift assay of wild-type and mutant HESX1.

Similar content being viewed by others

References

  1. Hermesz, E., Mackem, S. & Mahon, K.A. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo. >Development 122, 41–52 (1996)

    CAS  PubMed  Google Scholar 

  2. Thomas, P. & Beddington, R.S.P. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo . Curr. Biol. 6, 1487–1496 (1996)

    Article  CAS  PubMed  Google Scholar 

  3. Thomas, P et al. Axis duplication and anterior identity in the mouse embryo. In Symposia on Quantitative Biology LXII, Cold Spring Harbor Press (in press)

  4. Valentino, K.L. & Jones, E.G. The early formation of the corpus callosum: a light and electron microscopic study in foetal and neonatal J. Neurocytol. 11, 583–609 (1992)

    Article  Google Scholar 

  5. Oliver, G. et al. Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development 121, 4045–4055 (1995)

    CAS  PubMed  Google Scholar 

  6. Walther, C. & Gruss, P. Pax6, a murine paired box gene, is expressed in the developing CNS. Development 113 , 1435–1449 (1991)

    CAS  PubMed  Google Scholar 

  7. Crossley, P.H. & Martin, G.R. The mouse Fgf8 gene encodes a family of polypeptides that is expressed in regions that direct outgrowth and patterning in the developing embryo. Development> 121, 439–451 (1995)

    CAS  PubMed  Google Scholar 

  8. Echelard, Y. et al. Sonic hedgehog, a member of a family of putative signalling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993)

    Article  CAS  PubMed  Google Scholar 

  9. Shimamura, K. et al. Longitudinal organization of the anterior neural plate and neural tube. Development 121, 3923–3933 (1995)

    CAS  PubMed  Google Scholar 

  10. Lazzaro, D. et al. The transcription factor TTF-1 is expressed as the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. Development 113, 1093–1104 (1991)

    CAS  PubMed  Google Scholar 

  11. Thomas, P.Q., Johnson, B.V., Rathjen, J. & Rathjen P.D. Sequence, genomic organization, and expression of the novel homeobox gene Hesx1. J. Biol. Chem. 270, 3869–3875 (1995)

    Article  CAS  PubMed  Google Scholar 

  12. Samokhvalov, I.M. et al. Genomic structure of the homeobox-containing gene XANF1. Doklady. Biol. Sci. 334, 12–14 ( 1994)

    Google Scholar 

  13. Smith, S.T. & Jaynes, J.B. A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. Development 122, 3141–3150 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Webb, G.C. et al. Hesx1, a homeobox gene expressed by murine embryonic stem cells, maps to mouse chromosome 14, bands A3-B. Genomics 18, 464–466 (1993)

    Article  CAS  PubMed  Google Scholar 

  15. Wales, J.K.H. & Quarrell, O.W.J. Evidence for possible Mendelian inheritance of septo-optic dysplasia. Acta Paediatr. 85, 391–392 (1996)

    Article  CAS  PubMed  Google Scholar 

  16. Wilson, D.S., Guenther, B., Desplan, C. & Kuriyan, J. High resolution crystal structure of a paired (Pax) class cooperative homeodomain dimer on DNA. Cell 82, 709–719 (1995)

    Article  CAS  PubMed  Google Scholar 

  17. Kissinger, C.R., Lui, B., Martin-Blanco, E., Kornberg, T.B. & Pabo, C.O. Crystal structure of an engrailed homeodomain-DNA complex at 2.8Å resolution: a framework for understanding homeodomain-DNA interactions. Cell 63, 579 –590 (1990)

    Article  CAS  PubMed  Google Scholar 

  18. Sornson, M.W. et al. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 384, 327–333 (1996)

    Article  CAS  PubMed  Google Scholar 

  19. Latinkic, B.V., et al. The Xenopus Brachyury promoter is activated by FGF and low concentrations of activin and suppressed by high concentrations of activin and by paired-type homeodomain proteins. Genes Dev. 11, 3265 –3276 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Reeves, D.L. Congenital absence of septum pellucidum. Bull. Johns Hopkins Hosp. 69, 61–71 (1941)

    Google Scholar 

  21. de Morsier, G. Etudes sur les dysraphies cranio-encephaliques: III. Agenesie du septum lucidum avec malformation du tractus optique: La dysplasie septo-optique. Schweizer Arch. Neurol. Psychiatr. 77, 267–292 (1956)

    CAS  Google Scholar 

  22. Hoyt, W.F. et al. Septo-optic dysplasia and pituitary dwarfism. Lancet 1, 893–894 (1970)

    Article  CAS  PubMed  Google Scholar 

  23. Brook, C.G.D. et al. Septo-optic dysplasia. Br. Med. J. 3, 811 –813 (1972)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Arslanian, S.A. et al. Hormonal, metabolic, and neuroradiologic abnormalities associated with septo-optic dysplasia. Acta Endocrinol. 107, 282–288 (1984)

    Article  CAS  PubMed  Google Scholar 

  25. Izenberg, N et al. The endocrine spectrum of septo-optic dysplasia. Clin. Pediatr. 23, 632–636 ( 1984)

    Article  CAS  Google Scholar 

  26. Roessmann, U. Septo-optic dysplasia (SOD) or DeMorsier syndrome. J. Clin. Neuro-ophthalmol. 9, 156–159 ( 1989)

    CAS  Google Scholar 

  27. Blethen, S.L. & Weldon, V.V. Hypopituitarism and septo-optic dysplasia in first cousins. Am. J. Med. Genet. 21, 123–129 (1985)

    Article  CAS  PubMed  Google Scholar 

  28. Benner, J.D. et al. Septo-optic dysplasia in two siblings. Am. J. Opthalmol. 109, 632–637 (1990)

    Article  CAS  Google Scholar 

  29. Freund, C.L. et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 91, 543–553 ( 1997)

    Article  CAS  PubMed  Google Scholar 

  30. Brunelli, S. et al. Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nature Genet. 2, 94–96 (1996)

    Article  Google Scholar 

  31. Lalwani, A.K. et al. Further elucidation of the structure of PAX3, and identification of two different point mutations within the PAX3 homeobox that cause Waardenburg syndrome Type I in two families. Am. J. Hum. Genet. 56, 75–83 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ma, L. et al. The molecular basis of Boston-type craniosynostosis: the Pro148-His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences. Hum. Mol. Genet. 5, 1915–1920 (1996)

    Article  CAS  PubMed  Google Scholar 

  33. Semina, E.V. et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genet. 14, 392–399 ( 1996)

    Article  CAS  PubMed  Google Scholar 

  34. Vastardis, H. et al. A human MSX1 homeodomain missense mutation causes selective tooth agenesis . Nature Genet. 13, 417–421 (1996)

    Article  CAS  PubMed  Google Scholar 

  35. Benassayag, C. et al. A homeodomain point mutation of the Drosophila proboscipedia protein provokes eye loss independently of homeotic function. Mech. Dev. 63, 187–198 ( 1997)

    Article  CAS  PubMed  Google Scholar 

  36. Fortin, A.S., Underhill, D.A. & Gros, P. Reciprocal effect of Waardenburg syndrome mutations on DNA binding by the PAX-3 paired domain and homeodomain. Hum. Mol. Genet. 6, 1781–1790 (1997)

    Article  CAS  PubMed  Google Scholar 

  37. Lam, K.S.L. et al. Hypothalamic defects in two adult patients with septo-optic dysplasia. Acta Endocrinol. 112, 305–309 (1986)

    Article  CAS  PubMed  Google Scholar 

  38. Roessmann, U. et al. Neuropathology of "septo-optic dysplasia" (de Morsier syndrome) with immunohistochemical studies of the hypothalamus and pituitary gland. J. Neuropathol. Exp. Neurol. 64, 597–608 (1987)

    Article  Google Scholar 

  39. Masera, N., Grant, D.B., Stanhope, R.G. & Preece, M.A. Diabetes insipidus with impaired osmotic regulation in septo-optic dysplasia and agenesis of the corpus callosum. Arch. Dis. Child 70, 51–53 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Young, I.D. et al. Agenesis of the corpus callosum and macrocephaly in siblings. Clin. Genet. 28, 225–230 (1985)

    Article  CAS  PubMed  Google Scholar 

  41. Rimoin, D.L. Growth problems and clinical advances. (eds Bergsma, D. & Schimke R.N.) 15 –29 (Alan Liss, New York, 1976).

    Google Scholar 

  42. Zaias, B. & Becker D. Septo-optic dysplasia: Developmental or acquired abnormality? A case report. Trans. Am. Neurol. Assoc. 103, 273–277 ( 1978)

    CAS  PubMed  Google Scholar 

  43. Radovic, S. et al. A mutation in the POU-Homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 257, 1115–1118 (1992)

    Article  Google Scholar 

  44. Varlet, I., Collignon, J. & Robertson, E.J. Nodal expression in the primitive endoderm is required for specification of the anterior axis during mouse gastrulation. Development 124, 1033–1044 (1997)

    CAS  PubMed  Google Scholar 

  45. Rhinn, M. et al. Sequential roles for Otx2 in visceral endoderm and neuroectoderm for forebrain and midbrain induction and specification. Development 125, 845–856 ( 1998)

    CAS  PubMed  Google Scholar 

  46. Narita, N., Bielinska, M. & Wilson, D.B. Wild-type endoderm abrogates the ventral developmental defects associated with GATA-4 deficiency in the mouse. Dev. Biol. 189 , 270–274 (1997)

    Article  CAS  PubMed  Google Scholar 

  47. Lee, S.M.K., Danielian, P.S., Fritsch, B. & McMahon, A.P. Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. Development 124 , 959–969 (1997)

    CAS  PubMed  Google Scholar 

  48. Shimamura, K. & Rubinstein, J.L.R. Inductive interactions direct early regionalization of the mouse forebrain. Development, 124, 2709–2718 (1997)

    CAS  PubMed  Google Scholar 

  49. Meyers, E.N., Lewandoski, M. & Martin, G.R. An Fgf8 mutant allelic series generated by Cre-and Flp-mediated recombination . >Nature Genet. 18, 136–142, (1998)

    Article  CAS  PubMed  Google Scholar 

  50. Zhadanov A.B. et al. Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues. Dev. Dyn. 202 , 354–364 (1995

    Article  CAS  PubMed  Google Scholar 

  51. Sheng H.Z. et al. Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 272, 1004–1007 (1996)

    Article  CAS  PubMed  Google Scholar 

  52. Gage, P.J. et al. The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. Mol. Endocrinol. 10, 1570–1581 (1996)

    CAS  PubMed  Google Scholar 

  53. Wu, W. et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nature Genet. 18, 147–149 (1998)

    Article  CAS  PubMed  Google Scholar 

  54. Kaufmann, M.H. The Atlas of Mouse Development. (Academic Press, London, 1994 )

    Google Scholar 

  55. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning. A Laboratory Manual. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989)

    Google Scholar 

  56. Reece, R.J. & Ptashne, M. Determinants of binding-site specificity among yeast C6 Zinc cluster Proteins. Science 261, 909–911 (1993)

    Article  CAS  PubMed  Google Scholar 

  57. Lehming, N., McGuire, S., Brickman, J.M. & Ptashne, M. Interactions of a Rel protein with its inhibitor. Proc. Natl. Acad. Sci. USA 92, 10242–10246 (1995)

    Article  CAS  PubMed  Google Scholar 

  58. Gillett, G.T. et al. Irradiation hybrids for human chromosome 11: characterization and use for generating region-specific markers in 11q14-q23. Genomics 15, 332–341 (1993)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Erlandsson for help with the ES cell work, R.L. Gardner and M.A. Sällström for blastocyst injections, S. Povey for help with the FISH analysis and MRC HGMP for use of equipment. We also thank G. Martin, A. McMahon, D. Wilkinson, R. Di Lauro and P. Gruss for probes, and S. Da Rocha and members of Biological Services and Histology at NIMR for excellent technical assistance. We particularly thank K. Mahon for sharing unpublished data. J.-P.M.-B., a recipient of a Lund-Oxford Developmental Biology Programme fellowship, thanks A. Björklund and T. Leanderson for continuous support. J.M.B. is an HFSP fellow. M.T.D. acknowledges funding support from C.G.D. Brook and the Special Trustees of the Middlesex Hospital. We are grateful to C.G.D. Brook, A. Aynsley-Green, M. Preece, R. Stanhope and P. Bareille for their help with the recruitment of patients. We also thank the patients and their families for their help in this study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Iain C. A. F. Robinson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dattani, M., Martinez-Barbera, JP., Thomas, P. et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19, 125–133 (1998). https://doi.org/10.1038/477

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/477

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