Figure 7.

Schematic drawing of proposed mechanism of metacarpophalangeal joint development and expression of Gdf5, Nog, and Bmp2 in mouse limbs corresponding to E12.5, E13.0, E13.5, and E14.5. Gdf5 induces longitudinal growth at the distal end of each element. Bmp inhibitor Nog is expressed in the cartilage anlagen and the joint interzone first, while Bmp2 is expressed later. Apoptosis, mechanical forces, and other factors lead to formation of a joint space. Boxes on left and right show proposed molecular pathogenesis for brachydactyly and SYM1, respectively. Reduction of GDF5 signal, as in the L441P mutant, results in reduced growth of phalanges and thus shortening of elements. Increased GDF5 signaling, as in the R438L mutant, or mutations in NOG, both result in the persistence of cartilage in the joint region and a deficiency in joint interzone formation. Clinically this results in lack of joint formation and thus SYM1.