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



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.

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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.

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  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


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Correspondence to Richard Maas.

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