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 wild-type 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.

中文翻译：

---

抑制星形胶质细胞FAK-JNK信号通过CNTF促进脑室下区神经发生。

星形胶质细胞源性睫状神经营养因子（CNTF）促进成人脑室下区（SVZ）神经发生。我们发现粘着斑激酶（FAK）和JNK，但不是ERK或P38，在体外抑制CNTF。在这里，我们定义了FAK-JNK途径及其对CNTF的调控，以及相关的白血病抑制因子（LIF）和白介素6（IL-6），它们以神经发生为代价促进干细胞更新。在成年雄性C57BL / 6小鼠中纹状体内注射FAK抑制剂FAK14可减少pJNK并增加含SVZ的脑室周围区域的CNTF表达。注射JNK抑制剂可增加CNTF而不影响LIF和IL-6，并增加SVZ增殖和成神经细胞形成。JNK抑制剂对CNTF-/-小鼠无作用，表明JNK通过抑制CNTF抑制SVZ神经发生。星形胶质细胞中FAK的诱导性缺失增加了SVZ CNTF和神经发生，但没有增加LIF和IL-6。纹状体内注射抑制剂提示P38降低LIF和IL-6表达，而ERK诱导CNTF和LIF。纹状体内FAK抑制可能通过ERK增加LIF，并通过不涉及P38的另一种途径增加IL-6。全身注射FAK14还可抑制JNK，同时增加CNTF，但不影响P38和ERK激活或LIF和IL-6的表达。重要的是，系统性FAK14在野生型C57BL / 6和CNTF + / +小鼠中增加了SVZ神经发生，但在CNTF-/-同窝幼仔中却没有，表明它通过上调CNTF发挥作用。