SPLTRAK Abstract Submission

Investigating The Role Of Gli Proteins During Regeneration Of Olfactory Epithelia

Anna Shirazyan
University of Michigan, , ,

The olfactory epithelium (OE) is comprised of several cell types, including olfactory sensory neurons (OSNs), sustentacular cells (SUS), and microvillar cells (MVC), which can be replenished by two presumed stem cell populations:  globose basal cells (GBCs), and horizontal basal cells (HBCs). While HBCs and GBCs both contribute to OE regeneration, the signaling pathways that control this process are not well understood. Recent work indicates that HBCs contain primary cilia, cellular organelles that coordinate signals from multiple pathways. Notably, primary cilia are essential for proper vertebrate Hedgehog (HH) signal transduction, making the HH pathway a candidate in the control of HBC function. Further, HH signaling is important in another chemosensory organ, the tongue, where HH pathway blockade results in abnormal taste bud maintenance. GLI proteins are the transcriptional effectors of the HH pathway – GLI1 functions exclusively as a transcriptional activator and is a target of HH signaling; GLI2 is the major transcriptional activator of the HH pathway; conversely, GLI3 acts largely as a transcriptional repressor. Preliminary data suggest that Gli2 and Gli3 are expressed in HBCs, and that Gli2 expression expands in the OE following severe injury. To assess possible GLI function in HBCs, we utilized doxycycline-inducible expression of a constitutively active form of GLI2 to stimulate the HH pathway specifically in HBCs (K5-rtTA; tetO-GLI2ΔN). Our data indicate that HBC-specific activation of GLI2 causes hyperproliferation of HBCs that are then unable to differentiate and reconstitute the OE after methimazole-induced injury. This suggests a novel contribution of GLI proteins to HBC-mediated OE regeneration. Future studies will investigate the roles of endogenous GLIs in HBC function.