Sonic Hedgehog Signaling is Negatively Regulated in Reactive Astrocytes Following Forebrain Stab Injury

Following injury, the brain undergoes a multicellular response where both neural and non-neural cell types engage in a collective effort to protect surviving cells, clear cellular debris, and return to tissues homeostasis. Astrocytes, critical neural cells responsible for a variety of functions in the brain, become reactive in response to central nervous system (CNS) injury. Reactive astrocytes undergo a wide spectrum of changes and are characterized by an upregulation of glial fibrillary acidic protein (GFAP), cellular hypertrophy, proliferation, and participation in glial scar formation, segregating healthy from damaged tissues. Understanding the molecular mechanisms and signaling pathways that coordinate the diverse functional properties of reactive astrocytes is key to developing therapeutic strategies to treat neural injuries. In the healthy, adult CNS, Sonic hedgehog (Shh) signaling is active in mature, differentiated astrocytes. After injury, Shh signaling has been shown to promote various cellular activities, including proliferation of adult neural stem and progenitor cells. Both SHH and its target gene, GLI1 have previously been shown to undergo injury-induced upregulation and promote neural repair, suggesting that Shh signaling may play a role in neural repair processes. Here, we investigated whether Shh signaling mediates the astrocyte responses to a forebrain stab injury. Surprisingly, we found that following an acute, focal injury reactive astrocytes exhibit a pronounced loss of Shh activity in a spatiotemporally-defined manner. Shh signaling is lost in reactive astrocytes at the lesion site, but persists in mild to moderately reactive astrocytes in distal tissues. Nevertheless, local pharmacological activation of the Shh signaling pathway in astrocytes mitigates inflammation, consistent with a neuroprotective role for Shh signaling after injury. Interestingly, we find that Shh signaling is restored to baseline levels two weeks after injury, a time during which acute inflammation has largely subsided, and lesions have matured. Taken together, these data suggest that endogenous Shh signaling in astrocytes is dynamically regulated in a context dependent manner. In addition, exogenous activation of the Shh pathway promotes neuroprotection mediated by reactive astrocytes.Ph.D., Biological Sciences -- Drexel University, 201