The Hedgehog (Hh) family of secreted signaling proteins plays fundamental roles in the patterning of ventral neuronal cell types of the brain and spinal cord, limb, teeth, lung, and many other structures. Loss of or decrease in the Hh signaling pathway activity results in severe developmental birth defects such as holopresencephaly (HPE), a striking malformation of head and brain that includes cyclopia and loss of midline forebrain and facial structures. In addition to developmental abnormalities, inappropriate activation of the Hh signaling pathway is also associated with several common types of human cancer including basal cell carcinoma, medulloblastoma, and primitive neuroectodermal tumors. An understanding of this pathway is crucial for us to prevent or remedy the abnormalities resulting from defective or unregulated Hh pathway activation.

Our long-term goal is to understand the molecular mechanisms by which the Hh signal is transduced and to determine the role of Hh signaling in pattern specification and tumor formation. Hedgehog signal is transmitted by its receptors (Pathed and Smoothened, membrane proteins) and ultimately activates the Gli2 and Gli3 transcriptional factors. Signal transduction between the receptors and the transcriptional factors requires many effector molecules that modulate the site specific proteolytic processing and activities of Gli2 and Gli3. Many effectors are required to In Drosophila, Hh signal is mediated by Cubitus Interruptus (Ci), a transcription factor with a centrally localized 5-zinc-finger domain responsible for DNA binding. In the absence of Hh signal, a significant fraction of Ci protein is proteolytically processed to generate a transcriptional repressor. The Ci processing requires the activity of cAMP-dependent protein kinase (PKA) and of Slimb, a subunit of the novel E3 ubiquitin-ligase called SCF complex. Hh signal stimulation blocks the Ci processing and activates its targets. Vertebrate homologs of Ci are Gli1, Gli2, and Gli3. Gli1 and Gli2 act positively, whereas Gli3 plays a negative role in the Hh pathway. Consistent with a negative role of Gli3 in the Hh pathway, we have shown that the majority of Gli3 protein is processed in the absence of Sonic hedgehog (Shh) signal, a member of the Hedgehog family. Like Ci, Gli3 processing is also dependent on PKA, although it is not known whether it also requires vertebrate Slimb gene function. Shh signaling inhibits Gli3 processing and also regulates its RNA levels, thus regulating the net output of Gli transcriptional activities. Many questions remain to be answered. How are Ci and Gli3 proteins processed? How is the processing of Gli3 and Ci proteins regulated by Hh signaling? How is the activity of Gli2 regulated by Hh signaling? We are currently using an integrative approach that includes biochemical, cell biological, and genetic techniques to address these questions.

For more information, please contact Dr. Wang at:
Email: baw2001@med.cornell.edu