Letter | Published:

Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation

Nature Genetics volume 24, pages 391395 (2000) | Download Citation

Subjects

Abstract

The composite structure of the mammalian skull, which forms predominantly via intramembranous ossification, requires precise pre- and post-natal growth regulation of individual calvarial elements. Disturbances of this process frequently cause severe clinical manifestations in humans. Enhanced DNA binding by a mutant MSX2 homeodomain results in a gain of function and produces craniosynostosis in humans1,2. Here we show that Msx2-deficient mice have defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina3 (PFM). Msx2−/− mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, post-natal deficits in Pth/Pthrp receptor (Pthr) signalling and in expression of marker genes for bone differentiation indicate that Msx2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with PFM, Msx2-mutant mice also display defective tooth, hair follicle and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Our results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75, 443–450 ( 1993).

  2. 2.

    , , & 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).

  3. 3.

    et al. Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Nature Genet. 24, 387–390 (2000).

  4. 4.

    et al. Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2-mediated craniosynostosis in humans. Dev. Biol. 205, 260–274 ( 1999).

  5. 5.

    et al. Ectopic Msx2 overexpression inhibits and Msx2 antisense stimulates calvarial osteoblast differentiation. Dev. Biol. 209, 298–307 (1999).

  6. 6.

    , & Reciprocal regulation of osteocalcin transcription by the homeodomain proteins Msx2 and Dlx5. Biochemistry 37, 16360–16368 ( 1998).

  7. 7.

    et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613–622 (1996).

  8. 8.

    et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8, 277–289 (1994).

  9. 9.

    et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663– 666 (1996).

  10. 10.

    et al. Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev. Biol. 175, 166–176 ( 1996).

  11. 11.

    Seizures associated with the Catlin mark. Neurology 11, 345–348 (1961).

  12. 12.

    et al. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nature Genet. 20, 251–258 (1998).

  13. 13.

    & The cells and molecules that make a cerebellum. Trends Neurosci. 21, 375–382 (1998).

  14. 14.

    Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders (Johns Hopkins University Press, Baltimore, 1998).

  15. 15.

    & Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development . Nature Genet. 6, 348– 356 (1994).

  16. 16.

    & FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Development 125, 4325–4333 (1998).

  17. 17.

    , & Expression patterns of the homeobox gene, Hox-8, in the mouse embryo suggest a role in specifying tooth initiation and shape. Development 115, 403– 420 (1992).

  18. 18.

    , , & FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78, 1017– 1025 (1994).

  19. 19.

    Mammary embryogenesis. in The Mammary Gland, Development, Regulation and Function (eds Neville, M.C. & Daniel, C.W.) 37– 66 (Plenum, New York, 1987).

  20. 20.

    et al. Regulation of Msx-1, Msx-2, Bmp-2, and Bmp-4 during foetal and postnatal mammary gland development. Development 122, 2729–2737 (1996).

  21. 21.

    , , & Digit tip regeneration correlates with regions of Msx1 (Hox 7) expression in fetal and newborn mice. Development 121 , 1065–1076 (1995).

  22. 22.

    , , & Hereditary cranium bifidium and symmetric parietal formina are the same entity . Am. J. Med. Genet. 35, 453– 458 (1990).

  23. 23.

    , & Aplasia cutis congenita and enlarged parietal foramina (Catlin marks) in a family. Acta Paediatr. 84, 701–702 (1995).

  24. 24.

    , & Syndromic foramina parietalia permagna . Am. J. Med. Genet. 78, 401– 405 (1998).

  25. 25.

    et al. Eya1 -deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nature Genet. 23, 113–117 (1999).

  26. 26.

    , & Epithelial cytodifferentiation and extracellular matrix formation in enamel free areas of the occlusal cusp during development of mouse molars: light and electron microscopic studies. Am. J. Anat. 184, 287–297 ( 1989).

  27. 27.

    et al. A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. J. Invest. Dermatol. 113, 523–532 ( 1999).

  28. 28.

    et al. Basal cell carcinomas in mice overexpressing Sonic hedgehog. Science 276, 817–821 ( 1997).

  29. 29.

    et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1 deficient mice. Genes Dev. 8, 2691–2703 (1994).

Download references

Acknowledgements

We thank M. Hardy-Falling and S. Müller-Röver for help analysing the hair follicle phenotype, and G. Martin, A. Broadus, K. Kratochwil, R. Segal and J. Glowacki for helpful discussions. This work was supported by an AHA Postdoctoral Fellowship and grant from the Ichiro Kanehara Foundation to I.S. and by NIH grant RO1 DE11697 to R.M.

Author information

Affiliations

  1. Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    • Ichiro Satokata
    • , Liang Ma
    • , Marianna Bei
    • , Ian Woo
    • , Shaun Heaney
    • , Heiko Peters
    •  & Richard Maas
  2. Department of Pediatrics, Niigata University School of Medicine, Asahimachi, Japan

    • Ichiro Satokata
    • , Kazumichi Nishizawa
    •  & Makoto Uchiyama
  3. Department of Oral Anatomy, Faculty of Dentistry, Niigata University, Gakkocho, Niigata, Japan

    • Hayato Ohshima
    •  & Takeyasu Maeda
  4. Department of Oral Anatomy, Tokyo Medical and Dental University, Faculty of Dentistry, Yushima, Tokyo, Japan

    • Yoshiro Takano
  5. Department of Biochemistry and Molecular Biology, U.S.C. School of Medicine and Norris Cancer Center, Los Angeles, California, USA

    • Zequn Tang
    •  & Robert Maxson

Authors

  1. Search for Ichiro Satokata in:

  2. Search for Liang Ma in:

  3. Search for Hayato Ohshima in:

  4. Search for Marianna Bei in:

  5. Search for Ian Woo in:

  6. Search for Kazumichi Nishizawa in:

  7. Search for Takeyasu Maeda in:

  8. Search for Yoshiro Takano in:

  9. Search for Makoto Uchiyama in:

  10. Search for Shaun Heaney in:

  11. Search for Heiko Peters in:

  12. Search for Zequn Tang in:

  13. Search for Robert Maxson in:

  14. Search for Richard Maas in:

Corresponding author

Correspondence to Richard Maas.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/74231

Further reading