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Brachydactyly types A2, B, and C caused by mutations in BRIb, Ror2, and GDF-5 respectively.
Images courtesy of Prof. Mundlos, MPI for Molecular Genetics, Berlin.

Ror2 is an orphan receptor that belongs to the Trk family of receptor tyrosine kinases characterized by the presence of extracellular Frizzled-like cysteine-rich domains. Extracellularly it also contains an immunoglobulin-like and a kringle domain. The cytoplasmic portion contains the tyrosine kinase-like, followed by serine/threonine- and proline-rich motifs [Masiakowski, 1992].
Receptor tyrosine kinases often have critical roles in particular cell lineages by initiating signaling cascades in those lineages. Although Ror2 has been shown to play crucial roles in developmental morphogenesis in different tissues, it remains elusive how Ror2 mediates these signaling events in detail.
Mutations in Ror2 result in Brachydactyly type B and Robinow Syndrome in human [DeChiara, 2000] [M Oldridge, 2000] [Patton2002]. This observation hints to a role of Ror2 in skeletal development. Interestingly, mutations in Growth and Differentiation Factor 5 (GDF-5) and its high affinity receptor BMP Receptor Type Ib (BRIb) produce similar phenotypes. Brachypodism in mice, Hunter-Thompson type chondrodysplasia and Brachydactyly type C in human result from defects in GDF-5. Mutations in BRIb cause Brachydactyly type A2 [Francis-West, 1999] [Storm, 1994] [Edwards, 2001] [Buxton, 2001] [Lehmann, 2003].
Recently we have shown that Ror2 interacts with BRIb via the CRD domain of Ror2. Additionally our results indicate that in the presence of Ror2, the GDF-5 stimulated Smad 1/5/8 signaling of BRIb is inhibited [Sammar, 2004].
Our current focus is to identify and understand Ror2 signaling events in the context of cartilage and bone formation.

Growth and Differentiation Factor 5 (GDF-5), a member of the bone morphogenetic protein (BMP) family, is produced in cartilage and joints, and induces chondroblastic and osteoblastic differentiation. Mice with mutations in the GDF-5 gene are known as brachypodism mice, which have short limbs and reduced number of bones and digits. Mutations in the human GDF-5 gene result in abnormalities known as acromesomelic chondrodysplasia (Hunter-Thompson type CHTT and Grebe type CGT). Other studies have shown that heterozygous mutations in the GDF-5 gene are responsible for autosomal dominant brachydactyly type C, in which shortening of middle phalanges is the principal finding. Thus GDF-5 acts specifically in the morphogenesis of limb skeleton. GDF-5 binds with high affinity to the BMP type Ib receptor (BR-Ib), which gets activated upon recruitment of BMP-type II receptor (BR-II). Since both of these receptors are used by several members of the BMP/GDF family of ligands, however the gene-knockout phenotypes of these ligands resemble a very distinct phenotype, it is evident that additional receptors or co-receptors are expressed, which specify distinct signaling cascades.
Using several expression cloning approaches we are currently screening for GDF-5 specific receptors (or co-receptors), distinct from the known BMP-receptors.