Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Neuroscience. 2010 Feb 17;165(4):1261-74. doi: 10.1016/j.neuroscience.2009.11.056. Epub 2009 Dec 1.
Ror1 and Ror2, a small family of tyrosine kinase receptors, have been implicated in multiple aspects of brain development in C. elegans and X. laevis. More recently, we have shown that these receptors modulate the rate of neurite elongation in cultured rat hippocampal neurons. However, no information is available regarding a potential role of these receptors in other developmental milestones in mammalian central neurons. Neither is the identity known of the Ror ligand(s) and/or the signal transduction pathway(s) in which they participate. Here we report that the down regulation of either Ror1 or Ror2 led to a significant decrease in synapse formation in cultured hippocampal neurons. Simultaneous targeting of Ror proteins, however, did not result in an additive phenotype. Our results also indicated that Ror1 and Ror2 physically interact in the mouse brain, suggesting that they might function as heterodimers in central neurons. In addition, these Ror complexes interacted with Wnt-5a mediating its effects on synaptogenesis. Together, these data suggest that Ror proteins play a key role in Wnt-5a-activated signaling pathways leading to synapse formation in the mammalian CNS.
Ror1 和 Ror2 是酪氨酸激酶受体的一个小家族，它们在秀丽隐杆线虫和非洲爪蟾的大脑发育的多个方面都有涉及。最近，我们发现这些受体可以调节培养的大鼠海马神经元的轴突伸长速度。然而，关于这些受体在哺乳动物中枢神经元的其他发育里程碑中是否具有潜在作用，以及它们参与的 Ror 配体和/或信号转导途径的信息还没有。在这里，我们报告说下调 Ror1 或 Ror2 会导致培养的海马神经元中突触形成显著减少。然而，同时靶向 Ror 蛋白并没有导致加性表型。我们的结果还表明，Ror1 和 Ror2 在小鼠大脑中相互作用，表明它们可能在中枢神经元中作为异源二聚体发挥作用。此外，这些 Ror 复合物与 Wnt-5a 相互作用，介导其对突触发生的影响。总之，这些数据表明 Ror 蛋白在 Wnt-5a 激活的信号通路中发挥关键作用，导致哺乳动物中枢神经系统中的突触形成。
