title: DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218.
abstract: Variations in the expression of the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction.
  
  
  
  With the use of postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors.
  
  
  
  We identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia.
  
  
  
  These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.
authors: Integrated Program in Neuroscience, Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada.
authors: Angélica
authors: A
authors: Torres-Berrío
authors: Department of Human Genetics; Montréal, Québec, Canada; McGill Group for Suicide Studies, Montréal, Québec, Canada.
authors: Juan Pablo
authors: JP
authors: Lopez
authors: Departments of Psychology ; Montréal, Québec, Canada.
authors: Rosemary C
authors: RC
authors: Bagot
authors: Douglas Mental Health University Institute; Montréal, Québec, Canada.
authors: Dominique
authors: D
authors: Nouel
authors: Douglas Mental Health University Institute; Montréal, Québec, Canada; Département de Toxicologie et risques chimiques, IRBA, Brétigny sur Orge, France.
authors: Gregory
authors: G
authors: Dal Bo
authors: Psychiatry, McGill University; Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada.
authors: Santiago
authors: S
authors: Cuesta
authors: Douglas Mental Health University Institute; Montréal, Québec, Canada.
authors: Lei
authors: L
authors: Zhu
authors: Douglas Mental Health University Institute; Montréal, Québec, Canada.
authors: Colleen
authors: C
authors: Manitt
authors: Douglas Mental Health University Institute; Montréal, Québec, Canada.
authors: Conrad
authors: C
authors: Eng
authors: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors: Helen M
authors: HM
authors: Cooper
authors: Psychiatry, McGill University; Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada.
authors: Kai-Florian
authors: KF
authors: Storch
authors: Psychiatry, McGill University; Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada; McGill Group for Suicide Studies, Montréal, Québec, Canada.
authors: Gustavo
authors: G
authors: Turecki
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors: Eric J
authors: EJ
authors: Nestler
authors: Psychiatry, McGill University; Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada. Electronic address: cecilia.flores@mcgill.ca.
authors: Cecilia
authors: C
authors: Flores
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000075389:DCC Receptor; D003865:Major Depressive Disorder / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012919:Social Behavior; D013315:Stress, Psychological / Q000150:complications; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; C501909:DCC protein, human; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins
keywords: Chronic social defeat stress; Guidance cue; Major depressive disorder; Neurodevelopment; Resilience; microRNA