Regulatory mechanisms governing GLI proteins in hedgehog signaling

The Hedgehog (Hh) signaling pathway is critical for regulating cell growth, survival, fate determination, and the overall patterning of both vertebrate and invertebrate body plans. Aberrations in Hh signaling are associated with congenital abnormalities and tumorigenesis. In vertebrates, Hh signaling depends uniquely on primary cilia, microtubule-based organelles that extend from the cell surface. Over the last 2 decades, studies have demonstrated that key molecules regulating Hh signaling dynamically accumulate in primary cilia via intraflagellar transport systems. Moreover, through the primary cilia, extracellular signals are converted to stabilize GLI2 and GLI3 that are transcription factors that play a central role in regulating Hh signaling at the post-translational modification level. Recent in vivo and anatomical studies have uncovered crucial molecules that facilitate the conversion of extracellular signals into the intracellular stabilization of GLI2/GLI3 via primary cilia, emphasizing their essential roles in tissue development and tumorigenesis. This review explores the regulatory mechanisms of GLI2/GLI3 with a focus on mammalian tissue development.