Nielsen Katherine M, Chaverra Martha, Hapner Sharon J, Nelson Branden R, Todd Valerie, Zigmond Richard E, Lefcort Frances
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA.
Mol Cell Neurosci. 2004 Apr;25(4):629-41. doi: 10.1016/j.mcn.2003.12.004.
Developing neurons encounter a panoply of extracellular signals as they differentiate. A major goal is to identify these extrinsic cues and define the mechanisms by which neurons simultaneously integrate stimulation by multiple factors yet initiate one specific biological response. Factors that are known to exert potent activities in the developing nervous system include the NGF family of neurotrophic factors, ciliary neurotrophic factor (CNTF), and pituitary adenylate cyclase-activating peptide (PACAP). Here we demonstrate that PACAP promotes the differentiation of nascent dorsal root ganglion (DRG) neurons in that it increases both the number of neural-marker-positive cells and axonogenesis without affecting the proliferation of neural progenitor cells. This response is mediated through the PAC1 receptor and requires MAP kinase activation. Moreover, we find that, in the absence of exogenously added PACAP, blockade of the PAC1 receptor inhibits neuronal differentiation. These data coupled with our finding that both PACAP and the PAC1 receptor are expressed during the peak period of neuronal differentiation in the DRG suggest that PACAP functions in vivo to promote the differentiation of nascent sensory neurons. Interestingly, we also demonstrate that the neurotrophic factors NT-3 and CNTF completely block the PACAP-induced neuronal differentiation. This points to the intricate integration of cellular signals by nascent neurons and, to our knowledge, is the first evidence for neurotrophic factor abrogation of a pathway regulated by G-protein-coupled receptors (GPCRs).
发育中的神经元在分化过程中会遇到大量细胞外信号。一个主要目标是识别这些外在线索，并确定神经元如何同时整合多种因素的刺激却引发一种特定生物学反应的机制。已知在发育中的神经系统中发挥强大作用的因素包括神经营养因子的NGF家族、睫状神经营养因子（CNTF）和垂体腺苷酸环化酶激活肽（PACAP）。在此我们证明，PACAP促进新生背根神经节（DRG）神经元的分化，因为它增加了神经标志物阳性细胞的数量和轴突形成，而不影响神经祖细胞的增殖。这种反应是通过PAC1受体介导的，并且需要丝裂原活化蛋白激酶激活。此外，我们发现，在没有外源添加PACAP的情况下，阻断PAC1受体可抑制神经元分化。这些数据，再加上我们发现PACAP和PAC1受体在DRG神经元分化高峰期均有表达，表明PACAP在体内发挥作用以促进新生感觉神经元的分化。有趣的是，我们还证明神经营养因子NT-3和CNTF完全阻断了PACAP诱导的神经元分化。这表明新生神经元对细胞信号进行了复杂的整合，据我们所知，这是神经营养因子废除由G蛋白偶联受体（GPCRs）调控的一条信号通路的首个证据。
