Banerjee Santanu, Hayer Katharina, Hogenesch John B, Granato Michael
Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Pharmacology and Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Development. 2015 Feb 15;142(4):753-62. doi: 10.1242/dev.115816.
Neural connectivity between the spinal cord and paired appendages is key to the superior locomotion of tetrapods and aquatic vertebrates. In contrast to nerves that innervate axial muscles, those innervating appendages converge at a specialized structure, the plexus, where they topographically reorganize before navigating towards their muscle targets. Despite its importance for providing appendage mobility, the genetic program that drives nerve convergence at the plexus, as well as the functional role of this convergence, are not well understood. Here, we show that in zebrafish the transcription factor foxc1a is dispensable for trunk motor nerve guidance but is required to guide spinal nerves innervating the pectoral fins, equivalent to the tetrapod forelimbs. In foxc1a null mutants, instead of converging with other nerves at the plexus, pectoral fin nerves frequently bypass the plexus. We demonstrate that foxc1a expression in muscle cells delineating the nerve path between the spinal cord and the plexus region restores convergence at the plexus. By labeling individual fin nerves, we show that mutant nerves bypassing the plexus enter the fin at ectopic positions, yet innervate their designated target areas, suggesting that motor axons can select their appropriate fin target area independently of their migration through the plexus. Although foxc1a mutants display topographically correct fin innervation, mutant fin muscles exhibit a reduction in the levels of pre- and postsynaptic structures, concomitant with reduced pectoral fin function. Combined, our results reveal foxc1a as a key player in the development of connectivity between the spinal cord and paired appendages, which is crucial for appendage mobility.
脊髓与成对附肢之间的神经连接是四足动物和水生脊椎动物卓越运动能力的关键。与支配轴肌的神经不同，支配附肢的神经在一个特殊结构——神经丛处汇聚，在那里它们进行拓扑重组，然后再朝着肌肉靶点延伸。尽管神经丛处的神经汇聚对于提供附肢运动能力很重要，但其驱动神经在神经丛处汇聚的遗传程序以及这种汇聚的功能作用仍未得到充分理解。在这里，我们表明，在斑马鱼中，转录因子foxc1a对于躯干运动神经的导向并非必需，但对于引导支配胸鳍（相当于四足动物的前肢）的脊神经是必需的。在foxc1a基因敲除突变体中，胸鳍神经不是在神经丛处与其他神经汇聚，而是经常绕过神经丛。我们证明，在界定脊髓与神经丛区域之间神经路径的肌肉细胞中表达的foxc1a可恢复神经丛处的汇聚。通过标记单个鳍神经，我们发现绕过神经丛的突变神经在异位位置进入鳍，但仍支配其指定的目标区域，这表明运动轴突可以独立于其通过神经丛的迁移来选择合适的鳍目标区域。尽管foxc1a突变体表现出拓扑结构正确的鳍神经支配，但突变鳍肌肉的突触前和突触后结构水平降低，同时胸鳍功能也降低。综合来看，我们的结果揭示foxc1a是脊髓与成对附肢之间连接发育的关键参与者，这对于附肢运动能力至关重要。
