title: Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress.
abstract: Genetic evidence suggests cell-type-specific functions for certain nucleoporins, and gene expression profiling has revealed that nucleoporin p62 (NUP62) transcripts are decreased in the prefrontal cortex of major depressives. Chronic stress, which can precipitate depression, induces changes in the architecture and plasticity of apical dendrites that are particularly evident in the CA3 region of the hippocampus. Genetically targeted translating ribosome affinity purification revealed a selective reduction in translated Nup62 transcripts in CA3 of chronically stressed mice, and the Nup62 protein content of nuclei extracted from whole hippocampus was found to be decreased in chronically stressed rats. In cultured cells, phosphorylation of a FAK/proline-rich tyrosine kinase 2 (PYK2) consensus site in the alpha-helical domain of NUP62 (human Y422) is shown to be associated with shedding of NUP62 from the nuclear pore complex (NPC) and/or retention of NUP62 in the cytoplasm. Increased levels of phospho-Y425 Nup62 were observed in cytoplasmic fractions of hippocampi from chronically stressed rats, and immunofluorescence microscopy revealed redistribution of activated Pyk2 to the perinuclear region of stressed pyramidal neurons. Depletion of Nup62 from cultured embryonic day 18 rat hippocampal and cortical neurons resulted in simplification and retraction of dendritic arbors, without disruption of axon initial segment integrity. Thus, at least two types of mechanisms--one affecting expression and the other association with the NPC--could contribute to loss of NUP62 from CA3 pyramidal neurons during chronic stress. Their combined actions may account for the enhanced responsiveness of CA3 apical dendrites to chronic stress and may either be pathogenic or serve to protect CA3 neurons from permanent damage.
authors.affiliation: Department of Pathology and.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Kinoshita
authors.affiliation: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10065; and Department of Psychology, University of Massachusetts, Boston, MA 02125.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Hunter
authors.affiliation: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10065; and.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gray
authors.affiliation: Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Roxana
authors.initials: R
authors.lastname: Mesias
authors.affiliation: Department of Psychology, University of Massachusetts, Boston, MA 02125 stave.kohtz@gmail.com mcewen@mail.rockefeller.edu.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
authors.affiliation: Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Benson
authors.affiliation: Department of Pathology and stave.kohtz@gmail.com mcewen@mail.rockefeller.edu.
authors.forename: D Stave
authors.initials: DS
authors.lastname: Kohtz
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D008562:Membrane Glycoproteins; C510282:NUP62 protein, mouse; D028861:Nuclear Pore Complex Proteins; C049312:nuclear pore protein p62; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse
keywords: chronic stress; dendrite retraction; hippocampus; nucleoporin p62; proline-rich tyrosine kinase 2