Nature 368, 639 - 643 (14 April 1994); doi:10.1038/368639a0

Limb alterations in brachypodism mice due to mutations in a new member of the TGF-superfamily

Elaine E. Storm^*, Thanh V. Huynh^†, Neal G. Copeland^‡, Nancy A. Jenkins^‡, David M. Kingsley^*§ & Se-Jin Lee^†

^* Department of Developmental Biology, Beckman Center B300, Stanford University School of Medicine, Stanford, California 94305-5427, USA
^† Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 725 North Wolfe St, Baltimore, Maryland 21205, USA
^‡ Mammalian Genetics Laboratory, ABL Basic Research Program, NCI Frederick Cancer Research and Development Center, PO Box B, Frederick, Maryland 21702-1201, USA
^§ To whom correspondence should be addressed.

THE mutation brachypodism (bp) alters the length and number of bones in the limbs of mice but spares the axial skeleton^1,2. It illustrates the importance of specific genes in controlling the morphogenesis of individual skeletal elements in the tetrapod limb^3,4. We now report the isolation of three new members of the transforming growth factor- (TGF-) superfamily⁵ (growth/differentiation factors (GDF) 5, 6 and 7) and show by mapping, expression patterns and sequencing that mutations in Gdf5 are responsible for skeletal alterations in bp mice. GDF5 and the closely related GDF6 and GDF7 define a new subgroup of factors related to known bone- and cartilage-inducing molecules, the bone morpho-genetic proteins (BMPs)⁶. Studies of Bmp5 mutations in short ear mice have shown that at least one other BMP gene is also required for normal skeletal development⁷. The highly specific skeletal alterations in bp and short ear mice suggest that different members of the BMP family control the formation of different morphological features in the mammalian skeleton.

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