title: Shh signaling guides spatial pathfinding of raphespinal tract axons by multidirectional repulsion.
abstract: 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 (Ptch1) 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-Ptch1 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, Ptch1 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.
authors: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors: Lijuan
authors: L
authors: Song
authors: Yuehui
authors: Y
authors: Liu
authors: Yang
authors: Y
authors: Yu
authors: Xin
authors: X
authors: Duan
authors: Shening
authors: S
authors: Qi
authors: Yaobo
authors: Y
authors: Liu
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D019556:COS Cells; D002421:Caudate Nucleus / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D059326:Serotonergic Neurons / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013116:Spinal Cord / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor