Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Abstract

Astrocyte-derived ciliary neurotrophic factor (CNTF) promotes adult subventricular zone (SVZ) neurogenesis. We found that focal adhesion kinase (FAK) and JNK, but not ERK or P38, repress CNTF in vitro. Here, we defined the FAK-JNK pathway and its regulation of CNTF in mice, and the related leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), which promote stem cell renewal at the expense of neurogenesis. Intrastriatal injection of FAK inhibitor, FAK14, in adult male C57BL/6 mice reduced pJNK and increased CNTF expression in the SVZ-containing periventricular region. Injection of a JNK inhibitor increased CNTF without affecting LIF and IL-6, and increased SVZ proliferation and neuroblast formation. The JNK inhibitor had no effect in CNTF−/− mice, suggesting that JNK inhibits SVZ neurogenesis by repressing CNTF. Inducible deletion of FAK in astrocytes increased SVZ CNTF and neurogenesis, but not LIF and IL-6. Intrastriatal injection of inhibitors suggested that P38 reduces LIF and IL-6 expression, whereas ERK induces CNTF and LIF. Intrastriatal FAK inhibition increased LIF, possibly through ERK, and IL-6 through another pathway that does not involve P38. Systemic injection of FAK14 also inhibited JNK while increasing CNTF, but did not affect P38 and ERK activation, or LIF and IL-6 expression. Importantly, systemic FAK14 increased SVZ neurogenesis in wildtype C57BL/6 and CNTF+/+ mice, but not in CNTF−/− littermates, indicating that it acts by upregulating CNTF. These data show a surprising differential regulation of related cytokines and identify the FAK-JNK-CNTF pathway as a specific target in astrocytes to promote neurogenesis and possibly neuroprotection in neurological disorders.

GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2–c-Fos–LIF signaling

“…3a). Previous research has confirmed that the MAPK signaling pathway is involved in the regulation of stemness 32,33 and the induction of LIF expression 34 . Hence, we explored the modulating effect of MAPK signaling on the GDF15-LIF pathway in GSCs.…”

Hesperidin ameliorates hypobaric hypoxia-induced retinal impairment through activation of Nrf2/HO-1 pathway and inhibition of apoptosis

“…It is well accepted that CNTF functions as a neuroprotective agent by promoting motor neuron survival, inhibiting microglial activation and attenuating microglia-derived oxidative stress 13 , 36 . Various glial cells especially astrocytes express CNTF in the neural retina and optic nerve head 37 – 39 . Several in vitro studies have shown that CNTF is capable of protecting both photoreceptors and ganglion cells from apoptosis 40 – 43 .…”

Inhibition of focal adhesion kinase increases adult olfactory stem cell self-renewal and neuroregeneration through ciliary neurotrophic factor

“…5B – C ) by 28% and 65%, respectively, compared to saline control in C57BL/6 mice. Thus, FAK inhibition increases CNTF like it does in the subventricular zone ( Keasey et al, 2013 ; Jia et al, 2018 ). FAK14 also increased the cell proliferation marker Ki67 mRNA expression ( Fig.…”

“…The CNTF null mice were produced by replacing the first exon of the CNTF gene with the bacterial lacZ gene, thus disrupting CNTF transcription while allowing expression of β-galactosidase (β-gal) protein which can be used as a reporter for “CNTF” expression ( Yang et al, 2008 ; Asan et al, 2003 ). The CNTF−/− mice have two copies and CNTF+/− have one copy of the reporter gene, which can be used to identify cells expressing even low levels of CNTF ( Yang et al, 2008 ; Kang et al, 2012 ; Langenhan et al, 2005 ; Jia et al, 2018 ). Both male and female CNTF littermate mice at 8–12 weeks old were used in the experiments.…”

“…We previously discovered that focal adhesion kinase (FAK), a non-receptor tyrosine kinase which mediates integrin signaling ( Schaller, 2010 ), represses CNTF expression in astroglioma C6 cells ( Keasey et al, 2013 ). Moreover, inhibition of FAK by systemic administration of FAK inhibitor, FAK14, enhances neurogenesis in the subventricular zone of adult naïve mice through upregulation of CNTF ( Jia et al, 2018 ). Here, we investigated whether this pathway also regulates adult regeneration in the mouse olfactory epithelium.…”