Polycystin‐1 stimulates skeletogenesis via TAZ‐mediated activation of RunX2

Abstract

Polycystin‐1 (PC1) plays an important regulatory role in bone growth and development, as evidenced by decreased bone density found in Pkd1 mutant mice. The activity of the transcription factor RunX2, the master control gene for osteoblast differentiation, is downregulated in Pkd1 mutant mice, suggesting a relationship between PC1 and RunX2. The mechanism of RunX2 activation by PC1, however, has not yet been established. We have shown that the carboxy‐terminal tail of PC1 (PC1‐CTT) is released by a γ‐secretase‐mediated cleavage and traffics to the nucleus, where it regulates the activity of nuclear signaling proteins. Using a novel ‘Co‐Activator Trap’ screen consisting of a library of Gal‐4 tagged transcription factors, the activity of which can be monitored by luciferase production, we identified the transcriptional co‐activator TAZ (Wwtr1) to be highly stimulated by the PC1‐CTT. The PC1‐CTT strongly stimulates RunX2 activity in a TAZ‐dependent manner, and enhances the ability of TAZ/RunX2 to recruit the transcriptional co‐activator p300. Loss of the two Pkd1 alleles in zebrafish results in a significant decrease in bone density, which can be partially rescued with reintroduction of the PC1‐CTT. TAZ is an essential co‐activator of RunX2 activity and may thus represent the missing mechanistic link between PC1 and RunX2.