Mutations in GDF-5, a member of the TGF-β superfamily, result in the autosomal recessive syndromes brachypod (bp) in mice and Hunter-Thompson and Grebe-type chondrodysplasias

The vertebrate appendicular skeleton consists of a series of elements that are separated by joints. Initially, the elements arise in the limb bud from the condensation of prechondrogenic mesenchyme, which subsequently differentiates to form cartilaginous templates of the respective elements, separated by joints (see Hinchliffe and Johnson, 1980 for review). In prospective long-bone elements, the chondrocytes are arranged in three zones: a central diaphyseal hypertrophic zone, flanked by two outer metaphyseal flattened cell zones and two proliferative epiphyseal rounded cell zones (Fell, 1925). The elements are surrounded by a fibrous perichondrium, which also possesses chondrogenic potential. Members of the TGF-β superfamily such as the Bone Morphogenetic Proteins (BMPs) and the closely related Growth and Differentiation Factors (GDFs) are fundamental players controlling skeletal development. This notion is based on three main lines of evidence. First, loss-of-function or gain-offunction studies of either the proteins themselves or their antagonists in the mouse and chick result in changes in skeletal development that appear to be a primary consequence of defective cartilage development rather than changes in embryonic patterning (Kingsley et al., 1992; Storm et al., 1994; Duprez et al., 1996; Storm and Kingsley, 1996; Zou et al., 1997; Brunet et al., 1998; Capdevila and Johnson, 1998; reviewed by Kingsley, 1994). Second, the ability of BMPs to promote endochondral bone formation, when implanted subcutaneously into adult rats, shows that some members of the family are able to initiate a cascade of skeletogenesis (reviewed by Carrington and Reddi, 1991; Rosen and Thies, 1992; Reddi, 1992). Finally, in vitro studies have shown that these factors can modulate chondrogenesis (for examples in the developing chick limb see Roark and Greer, 1994; Chen et al., 1991). GDF-5 (also known as CDMP-1) is one member of the family that has received particular attention as there are naturally occurring mutations in both humans and mice (Grüneberg and Lee, 1973; Storm et al., 1994; Storm and Kingsley, 1996; Thomas et al., 1996, 1997; Polinkovsky et al., 1997). These result in defects in the development of the 1305 Development 126, 1305-1315 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV4009