Interestingly, STAT3 independently from its transcrip Ixazomib tional function is necessary to maintain normal mito chondrial bioenergetic function, which is dependent on Ser 727 whose phosphorylated form is highly enriched in mitochondria, reviewed in. This mechanism is also present in cortical astrocytes. In light of our findings, it is possible that integrin ligand binding pro motes mitochondrial function through FAK JNK mediated STAT3 phosphorylation. Whether and how the mitochondrial effects of STAT3 might affect CNTF e pression remains to be determined. CNTF has also re cently been found to normalize mitochondrial function in diabetic conditions. This raises the possibility that under pathological conditions that reduce Ser 727 activity, CNTF and Thy 1 inhibition increases CNTF.

Neuronal loss in the adult mouse brain induces CNTF within hours possibly by disinhibition of Thy 1. It remains to be determined whether the other integrin substrates which inhibited CNTF e pression in vitro play a similar role in the CNS. Laminin is produced by astrocytes and neurons, vitronectin by endothelial cells and fibro nectin is associated with astrocytes. FAK plays key roles during nervous system development but its role and that of downstream JNK in adult neurogenesis had not been investigated. Importantly, in hibition of FAK with systemic drugs rapidly induced CNTF protein e pression which was biologically active as suggested by the increased formation of new neuroblasts in the adult mouse SVZ. This is consistent with our find ings that endogenous CNTF enhances proliferation of CNTF e pression is disinhibited in part to maintain mito chondrial function.

The function of CNTF continues to be elucidated with evidence of its role e tending to stimulation of mitochondrial bioenergetic function via NF kB signal ing as well as regulating neurogenesis and neuroprotection. With such diverse functions and as a mediator of critical protective STAT3 signaling in neurons, it is likely that several molecular mecha nisms e ist that lead to CNTF transcription. The role of neural Thy 1 is poorly understood despite being highly enriched in the brain and e clusively present on neurons. We identify Thy 1 as one of the neur onal ligands that mediates contact dependent repression of CNTF in astrocytes.

This is consistent with the finding that Thy 1 increases 100 Drug_discovery fold during early post natal de velopment in the CNS when CNTF e pression stays low, whereas it increases greatly in the peripheral nervous system during a similar time frame. Thy 1 binds to astrocytic vB3 integrin to activate FAK resulting in mor phological changes and cell cell attachment. Thy 1 can bind directly to vB5 integrin in lung fibroblasts, consistent with our findings that vB5 integrin represses progenitors in the SVZ without affecting normal neuronal cell fate choice. Our data are also consistent with the finding that SVZ neurogenesis is dependent on STAT3.