13-P113 Mutation of Furin cleavage sites in Drosophila BMPs

Gli repressor formation via Protein kinase A (PKA) activation. In the current study, we generated a chondrocyte-specific knockout mouse strain of Suppressor of Fused (Sufu) and demonstrated that loss of Sufu leads to elevated expression of Hh target genes, Gli1 and Patched 1 (Ptch1), in the growth plate. Histological analysis illustrated an increase of proliferating cells and a reduction of the hypertrophic zone in Sufu-deficient growth plate mimicking that seen in Ptch1 knockout mice. These observations indicate that Sufu plays a negative role in Hh signaling during chondrocyte development. Furthermore, explant culture studies revealed that Sufu is a key regulator in controlling the effect of PTHrP on chondrocyte differentiation. In vertebrates, primary cilia are required for proper control of Gli activities in Hh signal transduction. Intriguingly, using micromass culture, we showed that PTHrP regulates Ptch1 expression through a cilia-independent mechanism during chondrocyte differentiation. We are currently investigating the molecular action of Sufu in PTHrP-dependent chondrocyte differentiation and the role of PTHrP in cilia-independent Hh signaling. The results of these studies will be presented.