Franks, N. E. | Search bioRxiv

bioRxiv2022

Gli2 and Gli3 Regulate Horizontal Basal Cell-Mediated Regeneration of the Olfactory Epithelium

The olfactory epithelium (OE) is a specialized neuroepithelium that is replenished by two stem cell populations: globose basal cells (GBCs) and horizontal basal cells (HBCs). Previous work indicated that HBCs contain primary cilia, organelles that mediate Hedgehog (HH) pathway activity. However, a role for HH signaling in HBCs has not been investigated. We find that GLI2 and GLI3, transcriptional effectors of the HH pathway, are expressed in HBCs in the adult OE and that their expression expands following injury. Further, Gli2-expressing descendants contribute to all major OE cell types during OE regeneration. HBC-specific expression of constitutively active GLI2 drives inappropriate HBC proliferation, alters HBC identity, and culminates in a failure of HBCs to differentiate into olfactory sensory neurons (OSNs) following injury. HBC- specific deletion of endogenous Gli2 and Gli3 results in decreased HBCs and OSNs following OE injury. These data identify GLI2 and GLI3 as key regulators of HBC-mediated OE regeneration.

cell biology↗

bioRxiv2021

Plexins Promote Hedgehog Signaling Through Their Cytoplasmic GAP Activity

Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide- ranging functions. Previous work has identified Neuropilins, established Semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require Plexin co- receptors to mediate Semaphorin signaling, but a role for Plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple Plexins promote Hedgehog signaling in NIH/3T3 fibroblasts and that Plexin loss-of-function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the Plexin GTPase activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that Plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that Plexin loss-of-function significantly reduces the response to Hedgehog pathway activation in the mouse dentate gyrus. Together, these data identify Plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.

developmental biology↗