Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation
Open accessAbstract
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 humans. 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 foramina (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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Functional haploinsufficiency of MSX2 causes PFM, and whole-body Msx2 knockout mice exhibit pleiotropic defects.
“Functional haploinsufficiency of MSX2 causes parietal foramina (PFM), and whole-body Msx2 knockout mice exhibit pleiotropic defects in bone mass and ectodermal organ formation22,23.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [22]
Msx2 deficient P30 mice exhibit an osteopenia phenotype with predominant osteoblast defects.
“Msx2 deficient P30 mice exhibit an osteopenia phenotype with predominant osteoblast defects.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [22]
Whole-body Msx2 deficient mice are viable but with a variety of malformations, including PFM, defective cerebellum, tooth, hair follicle, and mammary gland development.
“In mouse models, whole-body Msx2 deficient mice are viable but with a variety of malformations, including PFM, defective cerebellum, tooth, hair follicle, and mammary gland development22.”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [22]
Cites
Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein
Vortkamp, A., Lee, K., Lanske, B., Segre, G. V., Kronenberg, H. M., & Tabin, C. J. (1996) · Science · doi:10.1126/science.273.5275.613 · Cited by 1,999 · see citing works
PTH/PTHrP Receptor in Early Development and Indian Hedgehog—Regulated Bone Growth
Lanske, B., Karaplis, A. C., Lee, K., Luz, A., Vortkamp, A., Pirro, A. E., Karperien, M., Defize, L. H. K., Ho, C., Mulligan, R. C., et al. (1996) · Science · doi:10.1126/science.273.5275.663 · Cited by 1,325 · see citing works
Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development
Satokata, I., & Maas, R. L. (1994) · Nature Genetics · doi:10.1038/ng0494-348 · Cited by 1,274 · see citing works
Self-citationLethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene.Preprint
Karaplis, A. C., Luz, A., Glowacki, J., Bronson, R. T., Tybulewicz, V. L. J., Kronenberg, H. M., & Mulligan, R. C. (1994) · Genes & Development · doi:10.1101/gad.8.3.277 · Cited by 1,151 · see citing works
van Genderen, C., Okamura, R., Fariñas, I., Quo, R. G., Parslow, T., Bruhn, L., & Grosschedl, R. (1994) · Genes & Development · doi:10.1101/gad.8.22.2691 · Cited by 1,031 · see citing works
McKusick, V. A. (1998) · Johns Hopkins University Press eBooks · doi:10.56021/9780801857423 · Cited by 769 · see citing works
Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia
Xu, P., Adams, J. C., Peters, H., Brown, M. C., Heaney, S., & Maas, R. L. (1999) · Nature Genetics · doi:10.1038/12722 · Cited by 725 · see citing works
Self-citationBasal Cell Carcinomas in Mice Overexpressing Sonic Hedgehog
Oro, A. E., Higgins, K. M., Hu, Z., Bonifas, J. M., Epstein, E. H., & Scott, M. P. (1997) · Science · doi:10.1126/science.276.5313.817 · Cited by 707 · see citing works
Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders
McKusick, V. A. (1998) · DigitalGeorgetown (Georgetown University Library) · Cited by 687 · see citing works
Jabs, E. W., Müller, U., Li, X., Ma, L., Luo, W., Haworth, I. S., Klisak, I. J., Sparkes, R. S., Warman, M. L., Mulliken, J. B., et al. (1993) · Cell · doi:10.1016/0092-8674(93)90379-5 · Cited by 673 · see citing works
Self-citationFGF5 as a regulator of the hair growth cycle: Evidence from targeted and spontaneous mutations
Hébert, J. M., Rosenquist, T., Götz, J., & Martin, G. R. (1994) · Cell · doi:10.1016/0092-8674(94)90276-3 · Cited by 589 · see citing works
van der Veen, C., Handjiski, B., Paus, R., Müller-Röver, S., Maurer, M., Eichmüller, S., Ling, G., Hofmann, U., Foitzik, K., & Mecklenburg, L. (1999) · Journal of Investigative Dermatology · doi:10.1046/j.1523-1747.1999.00740.x · Cited by 553 · see citing works
The cells and molecules that make a cerebellum
Goldowitz, D. (1998) · Trends in Neurosciences · doi:10.1016/s0166-2236(98)01313-7 · Cited by 493 · see citing works
Bei, M., & Maas, R. L. (1998) · Development · doi:10.1242/dev.125.21.4325 · Cited by 374 · see citing works
Self-citationFunctional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification
Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., & Maxson, R. E. (2000) · Nature Genetics · doi:10.1038/74224 · Cited by 315 · see citing works
Self-citationProgressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice
Pennacchio, L. A., Bouley, D. M., Higgins, K. M., Scott, M. P., Noebels, J. L., & Myers, R. (1998) · Nature Genetics · doi:10.1038/3059 · Cited by 297 · see citing works
MacKenzie, A., Ferguson, M. W. J., & Sharpe, P. T. (1992) · Development · doi:10.1242/dev.115.2.403 · Cited by 294 · see citing works
Light and Electron Microscopic Studies
Bjerkfis, I. (1977) · Cited by 261 · see citing works
Amizuka, N., Karaplis, A. C., Henderson, J. E., Warshawsky, H., Lipman, M. L., Matsuki, Y., Ejiri, S., Tanaka, M. W., Izumi, N., Ozawa, H., et al. (1996) · Developmental Biology · doi:10.1006/dbio.1996.0104 · Cited by 253 · see citing works
Digit tip regeneration correlates with regions of Msx1 (Hox 7) expression in fetal and newborn mice
Reginelli, A. D., Wang, Y.-Q., Sassoon, D. A., & Muneoka, K. (1995) · Development · doi:10.1242/dev.121.4.1065 · Cited by 230 · see citing works
Liu, Y., Tang, Z., Kundu, R. K., Wu, L., Luo, W., Zhu, D., Sangiorgi, F. O., Snead, M. L., & Maxson, R. E. (1999) · Developmental Biology · doi:10.1006/dbio.1998.9114 · Cited by 201 · see citing works
Self-citationMa, L. (1996) · Human Molecular Genetics · doi:10.1093/hmg/5.12.1915 · Cited by 174 · see citing works
Self-citationRegulation of Msx-1, Msx-2, Bmp-2 and Bmp-4 during foetal and postnatal mammary gland development
Phippard, D., Weber-Hall, S. J., Sharpe, P. T., et al. (1996) · Development · doi:10.1242/dev.122.9.2729 · Cited by 167 · see citing works
Reciprocal Regulation of Osteocalcin Transcription by the Homeodomain Proteins Msx2 and Dlx5
Newberry, E. P., Latifi, T. N., & Towler, D. A. (1998) · Biochemistry · doi:10.1021/bi981878u · Cited by 141 · see citing works
EctopicMsx2Overexpression Inhibits andMsx2Antisense Stimulates Calvarial Osteoblast Differentiation
Dodig, M., Tadić, T., Kronenberg, M. S., Đačić, S., Liu, Y.-H., Maxson, R., Rowe, D. W., & Lichtler, A. C. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9258 · Cited by 120 · see citing works
Self-citationSakakura, T. (1987) · Springer eBooks · doi:10.1007/978-1-4899-5043-7_2 · Cited by 100 · see citing works
Ahmad, M., Haque, M. F. U., Ahmad, W., Abbas, H., Haque, S., Krakow, D., Rimoin, D. L., Lachman, R. S., & Cohn, D. H. (1998) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19980806)78:5 · Cited by 64 · see citing works
Hereditary cranium bifidum and symmetric parietal foramina are the same entity
Little, B. B., Knoll, K. A., Klein, V. R., et al. (1990) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320350402 · Cited by 47 · see citing works
Sakakura, Y., Fujiwara, N., & Nawa, T. (1989) · American Journal of Anatomy · doi:10.1002/aja.1001840404 · Cited by 24 · see citing works
Aplasia cutis congenita and enlarged parietal foramina (Catlin marks) in a family
Preis, S., Engelbrecht, V., & Lenard, H. (1995) · Acta Paediatrica · doi:10.1111/j.1651-2227.1995.tb13735.x · Cited by 23 · see citing works
Seizures associated with the Catlin mark
Kite, W. C. (1961) · Neurology · doi:10.1212/wnl.11.4.345 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Molecular Mechanisms Regulating Hair Follicle Development
Millar, S. E. (2002) · Journal of Investigative Dermatology · doi:10.1046/j.0022-202x.2001.01670.x · Cited by 967 · see citing works
Genetic Control of Bone Formation
Karsenty, G., Kronenberg, H. M., & Settembre, C. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.042308.113308 · Cited by 667 · see citing works
Cranial neural crest and the building of the vertebrate head
Santagati, F., & Rijli, F. M. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1221 · Cited by 461 · see citing works
Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification
Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., & Maxson, R. E. (2000) · Nature Genetics · doi:10.1038/74224 · Cited by 315 · see citing works
Self-citationMsx homeobox gene family and craniofacial development
ALAPPAT, S., ZHANG, Z. Y., & CHEN, Y. P. (2003) · Cell Research · doi:10.1038/sj.cr.7290185 · Cited by 278 · see citing works
Depew, M. J., Tucker, A. S., & Sharpe, P. T. (2002) · Mouse Development · doi:10.1016/b978-012597951-1/50023-8 · Cited by 259 · see citing works
Wnt signaling mediates regional specification in the vertebrate face
Brugmann, S. A., Goodnough, L. H., Gregorieff, A., Leucht, P., ten Berge, D., Fuerer, C., Clevers, H., Nusse, R., & Helms, J. A. (2007) · Development · doi:10.1242/dev.005132 · Cited by 213 · see citing works
Signals and switches in mammalian neural crest cell differentiation
Bhatt, S., Diaz, R., & Trainor, P. A. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008326 · Cited by 200 · see citing works
Reciprocal Roles of Msx2 in Regulation of Osteoblast and Adipocyte Differentiation
Ichida, F., Nishimura, R., Hata, K., Matsubara, T., Ikeda, F., Hisada, K., Yatani, H., Cao, X., Komori, T., Yamaguchi, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403621200 · Cited by 173 · see citing works
Blank, M. C., Grinberg, I., Aryee, E., Laliberte, C., Chizhikov, V. V., Henkelman, R. M., & Millen, K. J. (2011) · Development · doi:10.1242/dev.054114 · Cited by 116 · see citing works
Biological Roles of Uterine Glands in Pregnancy
Spencer, T. (2014) · Seminars in Reproductive Medicine · doi:10.1055/s-0034-1376354 · Cited by 115 · see citing works
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Mishina, Y., & Snider, T. N. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.01.019 · Cited by 114 · see citing works
Aïoub, M., Lézot, F., Molla, M., Castaneda, B., Robert, B., Goubin, G., Néfussi, J. R., & Berdal, A. (2007) · Bone · doi:10.1016/j.bone.2007.07.023 · Cited by 91 · see citing works
Msx2 Exerts Bone Anabolism via Canonical Wnt Signaling
Cheng, S.-L., Shao, J.-S., Cai, J., Sierra, O. L., & Towler, D. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800851200 · Cited by 89 · see citing works
Cheng, S.-L., Behrmann, A., Shao, J.-S., Ramachandran, B., Krchma, K., Bello Arredondo, Y., Kovacs, A., Mead, M., Maxson, R., & Towler, D. A. (2014) · Diabetes · doi:10.2337/db14-0326 · Cited by 77 · see citing works
Self-citationMsx2 mediates the inhibitory action of TNF-α on osteoblast differentiation
Lee, H.-L., Yi, T., Woo, K. M., Ryoo, H.-M., Kim, G.-S., & Baek, J.-H. (2010) · Experimental and Molecular Medicine · doi:10.3858/emm.2010.42.6.045 · Cited by 64 · see citing works
Sun, J., Ishii, M., Ting, M.-C., & Maxson, R. (2013) · Development · doi:10.1242/dev.085225 · Cited by 57 · see citing works
Self-citationMSX2 in ameloblast cell fate and activity
Babajko, S., de La Dure-Molla, M., Jedeon, K., & Berdal, A. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2014.00510 · Cited by 40 · see citing works
Mirzayans, F., Lavy, R., Penner-Chea, J., & Berry, F. B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049095 · Cited by 36 · see citing works
Ma, Q., Wang, S., Xue, H., Ni, L., Yuan, P., Shen, Y., Zheng, B., Wang, Q., Zhang, J., Wang, H., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61938-0 · Cited by 15 · see citing works
- Authors
- Satokata, I., Ma, L., Ohshima, H., Bei, M., Woo, I., Nishizawa, K., Maeda, T., Takano, Y., Uchiyama, M., Heaney, S., Peters, H., Tang, Z., Maxson, R., & Maas, R.
- Affiliations
- Brigham and Women's Hospital (US)
- Niigata University (JP)
- Tokyo Medical and Dental University (JP)
- University of Southern California (US)
- Corresponding author
- Maas, Richard
- ORCID
- Venue
- Nature Genetics
- Published
- 2000-04
- Volume
- 24
- Issue
- 4
- Pages
- 391-395
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1541819796
- Cited by
- 737
- References
- 31
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 10 · 2023: 16 · 2022: 13 · 2021: 18 · 2020: 26 · 2019: 16 · 2018: 17 · 2017: 13 · 2016: 21 · 2015: 23 · 2014: 33 · 2013: 29 · 2012: 30
- FWCI
- 25.95
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- National Institute of Dental and Craniofacial Research (R01 DE11697, R01DE011697)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- Msx2, homeodomain transcription factor, craniosynostosis, intramembranous ossification, endochondral ossification, chondrogenesis, bone formation, tooth development, hair follicle development, mammary gland development, seizures, cerebellar development
- MeSH terms
- Abnormalities, Multiple, Animals, Bone and Bones, Bone Development, Cartilage, Cell Differentiation, Cell Division, Cerebellum, DNA-Binding Proteins, Ectodermal Dysplasia, Mammary Glands, Animal, Mice, Mutant Strains, Phenotype, Seizures, Tooth Abnormalities, Mice, Knockout, Homeodomain Proteins, Hair Follicle, Chondrocytes, Mice
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