| Aggrecan is the large aggregating chondroitin sulfate proteoglycan found in the extracellular matrix (ECM) of hyaline cartilage (53). In the lethal chicken mutation nanomelia, it is an aggrecan deficiency that leads to severe skeletal defects. The aggrecan defect has been identified as a premature stop codon, which produces a truncated core protein precursor that lacks the C-terminal G3 and a part of the chondroitin sulfate domain (28). As a result, aggrecan fails to be secreted and the resulting ECM, lacking aggrecan, fails to function normally. Immunolocalization studies show the aggrecan precursor to be arrested in the endoplasmic reticulum and neither translocated to more distal parts of the secretory pathway such as the perinuclear Golgi nor secreted into the ECM (51). These observations suggest that the missing domains are important for the progress of aggrecan through the secretory pathway.;For studies of movement through the secretory pathway, genetic constructs with or without the C-terminal domain absent in the nanomelic chicken, CS-G3 and CS respectively, were used in transient transfection experiments. These studies were designed to establish the role of specific aggrecan domains, and particularly G3, in the progression of aggrecan through the secretory pathway. (Abstract shortened by UMI.)... |
