Kuruvilla Rejji, Zweifel Larry S, Glebova Natalia O, Lonze Bonnie E, Valdez Gregorio, Ye Haihong, Ginty David D
Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell. 2004 Jul 23;118(2):243-55. doi: 10.1016/j.cell.2004.06.021.
A fundamental question in developmental biology is how a limited number of growth factors and their cognate receptors coordinate the formation of tissues and organs endowed with enormous morphological complexity. We report that the related neurotrophins NGF and NT-3, acting through a common receptor, TrkA, are required for sequential stages of sympathetic axon growth and, thus, innervation of target fields. Yet, while NGF supports TrkA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT-3 cannot. Interestingly, final target-derived NGF promotes expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT-3. We propose that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TrkA internalization, trafficking, and retrograde axonal signaling.
发育生物学中的一个基本问题是，数量有限的生长因子及其同源受体如何协调形成形态极其复杂的组织和器官。我们报告，相关的神经营养因子NGF和NT-3通过共同受体TrkA发挥作用，是交感神经轴突生长的连续阶段以及因此对靶区域的神经支配所必需的。然而，虽然NGF支持TrkA内化以及从远端轴突到细胞体的逆行信号传导以促进神经元存活，但NT-3却不能。有趣的是，最终靶标来源的NGF促进p75神经营养因子受体的表达，进而导致轴突对中间靶标来源的NT-3的敏感性降低。我们提出，一个分级的神经营养因子信号级联以一种依赖于对TrkA内化、运输和逆行轴突信号传导的差异控制的方式，协调交感神经轴突生长、靶标神经支配和存活的连续阶段。
