Role of primary cilia in the activation of Gli transcription factors in Hedgehog signaling

Hedgehog (Hh) signaling is involved in embryonic development and tissue regeneration, and its dysregulation can lead to cancer and developmental defects. The final step in the Hh signaling cascade is the activation of Gli transcription factors. Despite intensive research, motivated by the importance of Gli proteins in development and cancer, their activation mechanism has remained elusive. One especially intriguing aspect of Gli activation is that it is dependent on the primary cilium, a tiny projection present on the surface of most mammalian cells. The goal of this project is to elucidate the molecular mechanisms of Gli protein activation, with particular emphasis on the role of primary cilia in this process.

Specifically, we will address the following questions:
1. What are the posttranslational modifications that define active Gli proteins? 
2. What amino acid sequence within Gli proteins enables their transport to cilia? 
3. Do activated Gli proteins form specific protein complexes in the cilia and what is the function of these complexes?