title: Novel axon projection after stress and degeneration in the Dscam mutant retina.
abstract: The Down syndrome cell adhesion molecule gene (Dscam) is required for normal dendrite patterning and promotes developmental cell death in the mouse retina. Loss-of-function studies indicate that Dscam is required for refinement of retinal ganglion cell (RGC) axons in the lateral geniculate nucleus, and in this study we report and describe a requirement for Dscam in the maintenance of RGC axon projections within the retina. Mouse Dscam loss of function phenotypes related to retinal ganglion cell axon outgrowth and targeting have not been previously reported, despite the abundance of axon phenotypes reported in Drosophila Dscam1 loss and gain of function models. Analysis of the Dscam deficient retina was performed by immunohistochemistry and Western blot analysis during postnatal development of the retina. Conditional targeting of Dscam and Jun was performed to identify factors underlying axon-remodeling phenotypes. A subset of RGC axons were observed to project and branch extensively within the Dscam mutant retina after eye opening. Axon remodeling was preceded by histological signs of RGC stress. These included neurofilament accumulation, axon swelling, axon blebbing and activation of JUN, JNK and AKT. Novel and extensive projection of RGC axons within the retina was observed after upregulation of these markers, and novel axon projections were maintained to at least one year of age. Further analysis of retinas in which Dscam was conditionally targeted with Brn3b or Pax6α Cre indicated that axon stress and remodeling could occur in the absence of hydrocephalus, which frequently occurs in Dscam mutant mice. Analysis of mice mutant for the cell death gene Bax, which executes much of Dscam dependent cell death, identified a similar axon misprojection phenotype. Deleting Jun and Dscam resulted in increased axon remodeling compared to Dscam or Bax mutants. Retinal ganglion cells have a very limited capacity to regenerate after damage in the adult retina, compared to the extensive projections made in the embryo. In this study we find that DSCAM and JUN limit ectopic growth of RGC axons, thereby identifying these proteins as targets for promoting axon regeneration and reconnection.
authors.affiliation: Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Fernandes
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, ID 83844, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Bloomsburg
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, ID 83844, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, ID 83844, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Billingslea
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, ID 83844, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Merrill
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Burgess
authors.affiliation: Flaum Eye Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Libby
authors.affiliation: University of Idaho, Department of Biological Sciences, Moscow, ID 83844, USA; WWAMI Medical Education Program, Moscow, ID 83844, USA. Electronic address: fuerst@uidaho.edu.
authors.forename: P G
authors.initials: PG
authors.lastname: Fuerst
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009416:Nerve Regeneration; D020221:Optic Nerve Injuries / Q000378:metabolism*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D013312:Stress, Physiological; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D015815:Cell Adhesion Molecules; C491735:Dscam protein, mouse; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4
keywords: Axon crush; Cell death; Optic nerve; Plasticity; Regeneration