Akshara Vykunta L&S Biological Sciences
Defining the Hedgehog Transcriptional Program
The Hedgehog (Hh) pathway directs gene expression programs that are essential for development and adult tissue homeostasis. However, misactivation of the Hedgehog pathway is known to drive cancer. Vertebrate Hh signals are transduced through the primary cilium, an antenna that projects from the surface of most cells. When the Hh pathway is off, the tumor suppressor Patched1 (Ptch1) localizes to cilia and inhibits Smoothened (Smo). Upon Hh pathway activation, Hh ligands bind to Ptch1, remove Ptch1 from cilia, and allow Smo to accumulate to cilia to activate the Gli family of transcriptional factors that induce the Hh transcriptional program. However, only Gli1 and Ptch1 have been defined as Hedgehog-responsive genes. Both medulloblastoma, the most common malignant brain tumor in children, and basal cell carcinoma (BCC), the most common cancer in the United States, are Hh-dependent but what defines physiologic and oncogenic Hedgehog signaling remains unknown. Thus, my work seeks to comprehensively define the Hedgehog transcriptional program to develop targeted therapeutics to improve patient outcomes.