Abstract
Reactive astrogliosis is a hallmark of many neurological disorders, yet its functions and molecular mechanisms remain elusive. Particularly, the upstream signaling that regulates pathological responses of astrocytes is largely undetermined. We used a mouse traumatic brain injury model to induce astrogliosis and revealed activation of ErbB receptors in reactive astrocytes. Moreover, cell-autonomous inhibition of ErbB receptor activity in reactive astrocytes by a genetic approach suppressed hypertrophic remodeling possibly through the regulation of actin dynamics. However, inhibiting ErbB signaling in reactive astrocytes did not affect astrocyte proliferation after brain injury, although it aggravated local inflammation. In contrast, active ErbB signaling in mature astrocytes of various brain regions in mice was sufficient to initiate reactive responses, reproducing characterized molecular and cellular features of astrogliosis observed in injured or diseased brains. Further, prevalent astrogliosis in the brain induced by astrocytic ErbB activation caused anorexia in animals. Therefore, our findings defined an unrecognized role of ErbB signaling in inducing reactive astrogliosis. Mechanistically, inhibiting ErbB signaling in reactive astrocytes prominently reduced Src and focal adhesion kinase (FAK) activity that is important for actin remodeling, although ErbB signaling activated multiple downstream signaling proteins. The discrepancies between the results from loss- and gain-of-function studies indicated that ErbB signaling regulated hypertrophy and proliferation of reactive astrocytes by different downstream signaling pathways. Our work demonstrated an essential mechanism in the pathological regulation of astrocytes and provided novel insights into potential therapeutic targets for astrogliosis-implicated diseases.
Highlights
Astrocytes, the principal macroglial cells in the central nervous system (CNS), are fundamental to brain function and health [1, 2]
Specific inhibition of ErbB receptor activity in reactive astrocytes in vivo In situ hybridization studies have revealed that the epidermal growth factor receptor (EGFR/ErbB1) and ErbB2 are expressed in astrocytes [23]
To confirm the specificity of megalencephalic leukoencephalopathy with subcortical cysts-1 (Mlc1)-tTA, an adenoassociated virus (AAV) harboring a tetracycline-responsive element (TRE)-yellow fluorescent protein (YFP) reporter was stereotaxically injected into the brain of 1-month-old Mlc1-tTA mice (Figure 1a)
Summary
Astrocytes, the principal macroglial cells in the central nervous system (CNS), are fundamental to brain function and health [1, 2]. Astrocytes’ pathological responses typically involve increased expression of glial fibrillary acidic protein (GFAP), cellular hypertrophy and enhanced proliferation This pattern is indicative of reactive astrogliosis, a hallmark of diverse neurological. Reactive astrocytes responding to pathological insults are distinct from normal astrocytes in morphology, functions and molecular profiles [1, 5,6,7] To explore these astrocytes’ regulatory mechanisms, many molecules have been investigated over the past few decades. Recent loss- and gain-of-function studies on genetically engineered mice show that FGF signaling inhibits astrocyte reactivity under both uninjured and injured conditions [18]. These findings emphasize that the upstream signaling that regulates astrogliosis remains largely undetermined
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