title: Schwann cells and deleted in colorectal carcinoma direct regenerating motor axons towards their original path.
abstract: After complete nerve transection, a major challenge for regenerating peripheral axons is to traverse the injury site and navigate toward their original trajectory. Denervated Schwann cells distal to the lesion site secrete factors promoting axonal growth and serve as an axonal substrate, yet whether Schwann cells also actively direct axons toward their original trajectory is unclear. Using live-cell imaging in zebrafish, we visualize for the first time how in response to nerve transection distal Schwann cells change morphology as axons fragment, and how Schwann cell morphology reverses once regenerating growth cones have crossed the injury site and have grown along distal Schwann cells outlining the original nerve path. In mutants lacking Schwann cells, regenerating growth cones extend at rates comparable with wild type yet frequently fail to cross the injury site and instead stray along aberrant trajectories. Providing growth-permissive yet Schwann cell-less scaffolds across the injury site was insufficient to direct regenerating growth cones toward the original path, providing compelling evidence that denervated Schwann cells actively direct regenerating axons across the injury site toward their original trajectory. To identify signals that guide regenerating axons in vivo, we examined mutants lacking the deleted in colorectal carcinoma (DCC) guidance receptor. In these dcc mutants, a significant fraction of regenerating motor axons extended along aberrant trajectories, similar to what we observe in mutants lacking Schwann cells. Thus, Schwann cell and dcc-mediated guidance are critical early during regeneration to direct growth cones across the transection gap and onto their original axonal trajectory.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6058.
authors.forename: Allison F
authors.initials: AF
authors.lastname: Rosenberg
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6058.
authors.forename: Jesse
authors.identifier: http://orcid.org/0000-0002-0932-0962
authors.initials: J
authors.lastname: Isaacman-Beck
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6058.
authors.forename: Clara
authors.initials: C
authors.lastname: Franzini-Armstrong
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6058 granatom@mail.med.upenn.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Granato
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D000075389:DCC Receptor; D020439:Growth Cones / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; D011956:Receptors, Cell Surface; D029961:Zebrafish Proteins; C506552:dcc protein, zebrafish
keywords: DCC; Schwann cell; peripheral nerve; regeneration; zebrafish