Abstract
BackgroundCiliary neurotrophic factor (CNTF) expression is repressed in astrocytes by neuronal contact in the CNS and is rapidly induced by injury. Here, we defined an inhibitory integrin signaling pathway.ResultsThe integrin substrates laminin, fibronectin and vitronectin, but not collagen, thrombospondin or fibrinogen, reduced CNTF expression in C6 astroglioma cells. Antibodies against αv and β5, but not α6 or β1, integrin induced CNTF. Together, the ligand and antibody specificity suggests that CNTF is repressed by αvβ5 integrin. Antibodies against Thy1, an abundant neuronal surface protein whose function is unclear, induced CNTF in neuron-astrocyte co-cultures indicating that it is a neuroglial CNTF repressor. Inhibition of the integrin signaling molecule Focal Adhesion Kinase (FAK) or the downstream c-Jun N-terminal kinase (JNK), but not extracellular regulated kinase (ERK) or p38 MAPK, greatly induced CNTF mRNA and protein expression within 4 hours. This selective inhibitory pathway phosphorylated STAT3 on its inhibitory ser-727 residue interfering with activity of the pro-transcription Tyr-705 residue. STAT3 can activate CNTF transcription because it bound to its promoter and FAK antagonist-induced CNTF was reduced by blocking STAT3. Microinjection of FAK inhibitor directly into the brain or spinal cord in adult mice rapidly induced CNTF mRNA and protein expression. Importantly, systemic treatment with FAK inhibitors over 3 days induced CNTF in the subventricular zone and increased neurogenesis.ConclusionsNeuron-astroglia contact mediated by integrins serves as a sensor to enable rapid neurotrophic responses and provides a new pharmacological avenue to exploit the neuroprotective properties of endogenous CNTF.
Highlights
Ciliary neurotrophic factor (CNTF) expression is repressed in astrocytes by neuronal contact in the CNS and is rapidly induced by injury
Glial CNTF is repressed through αvβ5 integrin To identify which integrins repress CNTF, we first tested various extracellular matrix (ECM) ligands with known differential integrin binding partners [21,34,35] in rat C6 astroglioma cells which express CNTF [36]
The low CNTF expression by C6 cells makes them a good cell model to study changes in CNTF expression whereas the very high levels in cultured primary astrocytes combined with the half-life of 7 hours of the CNTF mRNA make it more difficult to detect modest changes under acute conditions
Summary
Ciliary neurotrophic factor (CNTF) expression is repressed in astrocytes by neuronal contact in the CNS and is rapidly induced by injury. Endogenous CNTF regulates the development of oligodendrocytes [1] and some neurons [2], synaptic function [3], and adult CNS neurogenesis [4,5]. CNTF is almost exclusively expressed in the nervous system, suggesting that its pharmacological induction might solve these problems. In the CNS, CNTF is produced at very low levels primarily by astrocytes [15] but little is known about mechanisms that regulate its expression. We found that a cAMP-reducing dopamine D2 agonist induces CNTF in the brain but not the spinal cord [5], indicating the need to find more universal regulation mechanisms
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