Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA.
J Neurosci. 2011 Feb 16;31(7):2371-81. doi: 10.1523/JNEUROSCI.4243-10.2011.
The sympathetic nervous system has served as an amenable model system to investigate molecular mechanisms underlying developmental processes in the nervous system. While much attention has been focused on neurotrophic factors controlling survival and connectivity of postmitotic sympathetic neurons, relatively little is known about signaling mechanisms regulating development of sympathetic neuroblasts. Here, we report that Frizzled3 (Fz3), a member of the Wnt receptor family, is essential for maintenance of dividing sympathetic neuroblasts. In Fz3(-/-) mice, sympathetic neuroblasts exhibit decreased proliferation and premature cell cycle exit. Fz3(-/-) sympathetic neuroblasts also undergo enhanced apoptosis, which could not be rescued by eliminating the proapoptotic factor, Bax. These deficits result in reduced generation of sympathetic neurons and pronounced decreases in the size of sympathetic chain ganglia. Furthermore, the axons of sympathetic neurons that persist in Fz3(-/-) ganglia are able to extend out of sympathetic ganglia toward distal targets, but fail to fully innervate final peripheral targets. The cell cycle exit, but not target innervation, defects in Fz3(-/-) mice are phenocopied in mice with conditional ablation of β-catenin, a component of canonical Wnt signaling, in sympathetic precursors. Sympathetic ganglia and innervation of target tissues appeared normal in mice lacking a core planar cell polarity (PCP) component, Vangl2. Together, our results suggest distinct roles for Fz3 during sympathetic neuron development; Fz3 acts at early developmental stages to maintain a pool of dividing sympathetic precursors, likely via activation of β-catenin, and Fz3 functions at later stages to promote innervation of final peripheral targets by postmitotic sympathetic neurons.
交感神经系统是一个易于处理的模型系统，可用于研究神经系统发育过程中的分子机制。虽然人们已经关注了控制有丝分裂后交感神经元存活和连接的神经营养因子，但对于调节交感神经母细胞发育的信号机制却知之甚少。在这里，我们报告说，Wnt 受体家族的成员 Frizzled3（Fz3）对于维持分裂中的交感神经母细胞是必不可少的。在 Fz3（-/-）小鼠中，交感神经母细胞表现出增殖减少和过早的细胞周期退出。Fz3（-/-）交感神经母细胞也经历增强的细胞凋亡，这不能通过消除促凋亡因子 Bax 来挽救。这些缺陷导致交感神经元生成减少和交感神经链神经节明显减小。此外，在 Fz3（-/-）神经节中持续存在的交感神经元轴突能够伸出交感神经节向远端靶标延伸，但不能完全支配最终的外周靶标。Fz3（-/-）小鼠中的细胞周期退出，但不是靶标支配缺陷，在条件性敲除交感前体细胞中β-连环蛋白（经典 Wnt 信号的组成部分）的小鼠中得到了类似的表现。缺乏核心平面细胞极性（PCP）成分 Vangl2 的小鼠中，交感神经节和靶组织的支配似乎正常。总之，我们的结果表明 Fz3 在交感神经元发育过程中具有不同的作用；Fz3 在早期发育阶段起作用，维持一个分裂的交感前体细胞池，可能通过激活β-连环蛋白，而 Fz3 在后期阶段起作用，促进有丝分裂后交感神经元对最终外周靶标的支配。
