title: Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration.
abstract: Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn2+) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn2+increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn2+accumulation in amacrine cell processes involves the Zn2+transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn2+chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn2+chelation extends for several days after nerve injury. These results show that retinal Zn2+dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn2+chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Lukas
authors.initials: L
authors.lastname: Andereggen
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Kenya
authors.initials: K
authors.lastname: Yuki
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Omura
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Hui-Ya
authors.initials: HY
authors.lastname: Gilbert
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Burcu
authors.initials: B
authors.lastname: Erdogan
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Asdourian
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Christine
authors.initials: C
authors.lastname: Shrock
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Silmara
authors.initials: S
authors.lastname: de Lima
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Ulf-Peter
authors.initials: UP
authors.lastname: Apfel
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Zhuo
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115; paul.rosenberg@childrens.harvard.edu larry.benowitz@childrens.harvard.edu.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.|Program in Neuroscience, Harvard Medical School, Boston, MA 02115.
authors.forename: Paul A
authors.identifier: 0000-0002-5185-1118
authors.initials: PA
authors.lastname: Rosenberg
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115; paul.rosenberg@childrens.harvard.edu larry.benowitz@childrens.harvard.edu.|F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115.|Program in Neuroscience, Harvard Medical School, Boston, MA 02115.|Department of Ophthalmology, Harvard Medical School, Boston, MA 02115.
authors.forename: Larry
authors.initials: L
authors.lastname: Benowitz
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D027682:Cation Transport Proteins; D002614:Chelating Agents / Q000494:pharmacology; D005021:Ethylamines / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009416:Nerve Regeneration; D009900:Optic Nerve / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012160:Retina / Q000502:physiology*; D013425:Sulfanilic Acids / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002614:Chelating Agents; D005021:Ethylamines; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C511824:N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine; D011725:Pyridines; C491177:Slc30a3 protein, mouse; D013425:Sulfanilic Acids; C000609871:ZX1 chelating agent; D015032:Zinc
keywords: amacrine cell; cell death; chelation; exocytosis; neuroprotection