McKinnon Randall D, Waldron Sean, Kiel Mary E
Department of Surgery (Neurosurgery), University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
J Neurosci. 2005 Apr 6;25(14):3499-508. doi: 10.1523/JNEUROSCI.5049-04.2005.
Receptors with tyrosine kinase activity (RTKs) control tissue growth and development in metazoans. How they generate cell-specific responses remains essentially unknown; one model proposes that distinct RTKs activate different second-messenger pathways, whereas a second proposes that all RTKs deliver a generic "go" signal to these pathways that is uniquely interpreted by downstream, cell-specific response competence factors. We examine pathway activation and pathway-specific responses downstream of PDGFalpha receptors, whose expression in the developing CNS identifies oligodendrocyte progenitor cells (OPCs) and whose activation controls OPC proliferation, migration, survival, and maturation. PDGFRalpha-null mice die in utero, and OPCs that emerge before their demise have migration and proliferation defects and rapidly differentiate into postmitotic oligodendrocytes in vitro. OPCs from hemizygous mice also undergo precocious differentiation, indicating a role for PDGFRalpha gene dosage in timing OPC maturation. The rescue of PDGFRalpha-null OPCs with PDGFRalpha transgenes revealed specific roles for the phosphatidylinositol 3-kinase (PI3K) and phospholipase Cgamma (PLCgamma) pathways and a distinct ligand concentration dependence. Activation of the PI3K pathway is required for PDGFRalpha-induced migration, whereas activation of both PI3K and PLCgamma are required for PDGFRalpha-induced proliferation. For proliferation, PI3K activation is required at low ligand concentration, whereas PLCgamma is required at high signal strength. Dose-response studies further demonstrate that PDGFRalpha activates PI3K at low ligand concentrations, whereas PLCgamma is activated at high signal strength. Thus, PDGFRalpha signaling acts like a rheostat rather than generic ON switch, with signal strength dictating pathway activation during OPC maturation.
具有酪氨酸激酶活性的受体（RTKs）控制着后生动物的组织生长和发育。它们如何产生细胞特异性反应基本上仍然未知；一种模型认为，不同的RTKs激活不同的第二信使途径，而另一种模型则认为，所有RTKs都向这些途径传递一个通用的“启动”信号，该信号由下游的细胞特异性反应能力因子进行独特的解读。我们研究了血小板衍生生长因子α受体（PDGFalpha受体）下游的信号通路激活和通路特异性反应，PDGFalpha受体在发育中的中枢神经系统中的表达可识别少突胶质细胞前体细胞（OPCs），其激活控制着OPCs的增殖、迁移、存活和成熟。PDGFRalpha基因敲除小鼠在子宫内死亡，在其死亡前出现的OPCs具有迁移和增殖缺陷，并在体外迅速分化为有丝分裂后少突胶质细胞。来自半合子小鼠的OPCs也会过早分化，这表明PDGFRalpha基因剂量在OPC成熟时间调控中发挥作用。用PDGFRalpha转基因拯救PDGFRalpha基因敲除的OPCs，揭示了磷脂酰肌醇3激酶（PI3K）和磷脂酶Cγ（PLCγ）信号通路的特定作用以及明显的配体浓度依赖性。PI3K信号通路的激活是PDGFRalpha诱导迁移所必需的，而PI3K和PLCγ的激活都是PDGFRalpha诱导增殖所必需的。对于增殖而言，低配体浓度时需要PI3K激活，而高信号强度时需要PLCγ激活。剂量反应研究进一步表明，PDGFRalpha在低配体浓度下激活PI3K，而在高信号强度下激活PLCγ。因此，PDGFRalpha信号传导的作用类似于变阻器，而不是通用的开启开关，信号强度决定了OPC成熟过程中的信号通路激活。
