Department of Psychiatry-CHUV, Center for Psychiatric Neuroscience, Prilly-Lausanne, Switzerland.
Eur J Neurosci. 2011 Oct;34(7):1053-61. doi: 10.1111/j.1460-9568.2011.07839.x. Epub 2011 Sep 6.
Acquisition of a mature dendritic morphology is critical for neural information processing. In particular, hepatocyte growth factor (HGF) controls dendritic arborization during brain development. However, the cellular mechanisms underlying the effects of HGF on dendritic growth remain elusive. Here, we show that HGF increases dendritic length and branching of rat cortical neurons through activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Activation of MAPK by HGF leads to the rapid and transient phosphorylation of cAMP response element-binding protein (CREB), a key step necessary for the control of dendritic development by HGF. In addition to CREB phosphorylation, regulation of dendritic growth by HGF requires the interaction between CREB and CREB-regulated transcription coactivator 1 (CRTC1), as expression of a mutated form of CREB unable to bind CRTC1 completely abolished the effects of HGF on dendritic morphology. Treatment of cortical neurons with HGF in combination with brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family that regulates dendritic development via similar mechanisms, showed additive effects on MAPK activation, CREB phosphorylation and dendritic growth. Collectively, these results support the conclusion that regulation of cortical dendritic morphology by HGF is mediated by activation of the MAPK pathway, phosphorylation of CREB and interaction of CREB with CRTC1.
获得成熟的树突形态对于神经信息处理至关重要。特别是，肝细胞生长因子（HGF）在大脑发育过程中控制树突分支。然而，HGF 对树突生长影响的细胞机制仍不清楚。在这里，我们表明 HGF 通过激活丝裂原活化蛋白激酶（MAPK）信号通路来增加大鼠皮质神经元的树突长度和分支。HGF 激活 MAPK 导致 cAMP 反应元件结合蛋白（CREB）的快速和瞬时磷酸化，这是 HGF 控制树突发育的关键步骤。除了 CREB 磷酸化之外，HGF 对树突生长的调节还需要 CREB 和 CREB 调节转录共激活因子 1（CRTC1）之间的相互作用，因为表达一种不能与 CRTC1 完全结合的突变形式的 CREB 完全消除了 HGF 对树突形态的影响。用 HGF 和脑源性神经营养因子（BDNF）联合处理皮质神经元，BDNF 是神经营养因子家族的一员，通过类似的机制调节树突发育，结果显示对 MAPK 激活、CREB 磷酸化和树突生长有相加效应。总的来说，这些结果支持了这样的结论，即 HGF 对皮质树突形态的调节是通过激活 MAPK 途径、CREB 磷酸化和 CREB 与 CRTC1 的相互作用来介导的。
