A role for ErbB signaling in the induction of reactive astrogliosis

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.

Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis

“…Furthermore, they induce the release of neuroregulins, mediators of their biological activity through the binding of the receptor tyrosine kinases that encloses the ErbB genes [ 56 , 57 ]. The ErbB receptor family is an important regulator of oligodendrogenesis, myelination, and serotonin brain levels [ 58 ]; interestingly, we found that the ErbB signalling was the second most significant canonical pathway resulting from our data. On the other hand, a Gene Ontology (GO) term enrichment analysis showed that all the DE miRNAs, TFs, and their target genes were involved in important immune functions and in the maintenance of neuronal homeostasis.…”

The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival

“…Interestingly, we have also previously detected a post-traumatic contralateral upregulation of S100A4 19 , both effects most probably following the spreading astrocytic activation, which occurs in focal brain injuries 49 , 50 and was also observed in our cryogenic lesion model 19 . Moreover, as it was recently demonstrated in a mouse brain injury model and human brain astrocytes, spreading astroglyosis can affect and be reciprocally regulated by the activation of ErbB receptors in reactive astrocytes 51 , 52 . Since S100A4 can be released from stressed astrocytes 19 and upregulate ErbB4 mRNA in cultured neurons (Fig 2 C), S100A4 present in the CL hemisphere of WT animals with brain injury might directly and/or by affecting astroglyosis modulate contralateral ErbB4 expression.…”

Internal enhancement of DNA damage by a novel bispecific antibody‐drug conjugate‐like therapeutics via blockage of mTOR and PD‐L1 signal pathways in pancreatic cancer

“…The EGFR family (EGFR also known as HER) is a subset of receptor tyrosine kinases that activate and regulate diverse processes, including cell survival, proliferation, differentiation, and migration . It has been shown to be activated in many epithelial cancers such as colorectal, breast, and lung cancers .…”