Decoding Ci: from partial degradation to inhibition.

Hedgehog is a morphogen, which is widely involved in the regulation of cell proliferation, differentiation and tissue patterning during development in both vertebrate and invertebrate, such as in coordination of eye, brain, gonad, gut and tracheal development. In invertebrate, Cubitus interruptus (Ci) modification process is the last identified step before transcriptional activation in the Hh signaling pathway. Ci can form a truncated repressor (Ci(R) /Ci75) or act as an activator (Ci(A) /Ci155) based on Hh gradient to regulate the expressions of target genes. The activity of Ci is mediated by different mechanisms, including processing, trafficking and degradation. While in vertebrate, Glioblastomas (Glis), homologs of Ci, play similar but more complex roles in the regulation of mammals Hh pathway. Hh signaling is responsible for a wide variety of processes during embryonic development and adult tissue homeostasis. Malfunction of Hh signaling could cause various diseases including birth defects and cancers. Enormous efforts were made in the past decades to explore the Hh pathway regulation and the results have provided us important insights into disease diagnosis and therapeutic treatment. In this review, we focus on a small branch of Hh pathway regulation based on studies in the Drosophila system, mainly about Ci degradation, aiming to explain how Ci is modified by different ubiquitin ligases due to the strong or moderate Hh signals and then been subjected to complete or partial degradation by proteasomes. Overall, we intend to offer an overview on how Ci responds to and relays Hh signals in a precise manner to control target genes expressions and ensures proper Hh signal transduction.