Shh signaling guides spatial pathfinding of raphespinal tract axons by multidirectional repulsion  

作　　者：Lijuan Song Yuehui Liu Yang Yu Xin Duan Shening Qi Yaobo Liu 

机构地区：[1]State Key Laboratory of Brain and Cognitive Sciences,Institute of Biophysics,Chinese Academy of Sciences,15 Datun Road,Beijing 100101,China [2]Department of Histology and Embryology,School of Basic Medicine,Lanzhou University,Lanzhou 730000,China

出　　处：《Cell Research》2012年第4期697-716,共20页细胞研究（英文版）

基　　金：Acknowledgments We greatly appreciate the support of Dr Shigang He （Institute of Biophyscis, Chinese Academy of Sciences, China） for facilitating this research. We also appreciate the generous gift of different Shh and Smo mutants from Drs Chin Chiang and Xi Huang （Vanderbilt University Medical Center, USA）, the Ptchl^loop2 construct from Dr Paola Bovolenta （Instituto Cajal （CSIC） and CIBER de Enfermedades Raras （CIBERER）, Spain）, the Lmxlb antibody from Dr Yuqian Ding （Tongji University, China） and the Pax6 antibody from Dr Zhenggang Yang （Fudan University, China）. We thank Dr Helen Cooper （University of Queensland, Australia） for critical reading of the manuscript. We thank Drs Javid A Dar and Junkui Ai （University of Pittsburgh, USA） for proofreading the manuscript. This study was supported by grants from the National Natural Science Foundation of China （30640006, 30771063, 30871425 and 30990261） and the Chinese Academy of Sciences （KSCX2-EW-Q- 11）.

摘　　要：Relatively little is known about the molecular mechanisms underlying spatial pathfinding in the descending serotonergic raphespinal tract （RST） in the developing spinal cord, one of the most important nerve pathways for pain, sensory and motor functions. We provide evidence that ventral floor plate-secreted Sonic hedgehog （Shh） is responsible for the establishment of decreasing gradients in both the anterior-to-posterior （A-P） and the medial- to-lateral （M-L） directions in the ventral spinal cord during serotonergic RST axon projection. Downstream components of the Shh pathway, Patched 1 （Ptchl） and Smoothened （Smo）, were expressed in the serotonergic caudal raphe nuclei and enriched in the descending serotonergic RST axons. Diffusible Shh repulsion of serotonergic RST axons was shown to be mediated by Shh-Ptchl interactions and derepression of Smo. Using a co-culture assay, we showed that A-P graded repulsion mediated by Shh signaling pushed the serotonergic axons caudally through the ventral spinal cord and M-L graded repulsion mediated by Shh signaling simultaneously restricted the serotonergic axons to the ventral and ventral-lateral funiculus. Prominent pathfinding errors of serotonergic RST axons were observed in various Shh, Ptchl and Smo mutants. We conclude that Shh signaling-mediated multidirectional repulsion is required to push descending serotonergic RST axons in the A-P direction, and to restrict these axons to the ventral and ventral-lateral funiculus in the M-L direction. This is the first demonstration that Shh signaling- mediated multidirectional repulsion of serotonergic RST axons maintains spatial axon pathfinding in the developing spinal cord.

关 键 词：SHH PATHFINDING raphespinal tract AXON REPULSION 

分 类 号：Q786[生物学—分子生物学] TN92[电子电信—通信与信息系统]