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

The mutation brachypodism (bp) alters the length and number of bones in the limbs of mice but spares the axial skeleton. It illustrates the importance of specific genes in controlling the morphogenesis of individual skeletal elements in the tetrapod limb. We now report the isolation of three new members of the transforming growth factor-beta (TGF-beta) superfamily (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 morphogenetic proteins (BMPs). Studies of Bmp5 mutations in short ear mice have shown that at least one other BMP gene is also required for normal skeletal development. 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.