title: Diversification of behavior and postsynaptic properties by netrin-G presynaptic adhesion family proteins.
abstract: BACKGROUND
  Vertebrate-specific neuronal genes are expected to play a critical role in the diversification and evolution of higher brain functions. Among them, the glycosylphosphatidylinositol (GPI)-anchored netrin-G subfamily members in the UNC6/netrin family are unique in their differential expression patterns in many neuronal circuits, and differential binding ability to their cognate homologous post-synaptic receptors.
  
  
  RESULTS
  To gain insight into the roles of these genes in higher brain functions, we performed comprehensive behavioral batteries using netrin-G knockout mice. We found that two netrin-G paralogs that recently diverged in evolution, netrin-G1 and netrin-G2 (gene symbols: Ntng1 and Ntng2, respectively), were responsible for complementary behavioral functions. Netrin-G2, but not netrin-G1, encoded demanding sensorimotor functions. Both paralogs were responsible for complex vertebrate-specific cognitive functions and fine-scale regulation of basic adaptive behaviors conserved between invertebrates and vertebrates, such as spatial reference and working memory, attention, impulsivity and anxiety etc. Remarkably, netrin-G1 and netrin-G2 encoded a genetic "division of labor" in behavioral regulation, selectively mediating different tasks or even different details of the same task. At the cellular level, netrin-G1 and netrin-G2 differentially regulated the sub-synaptic localization of their cognate receptors and differentiated the properties of postsynaptic scaffold proteins in complementary neural pathways.
  
  
  CONCLUSIONS
  Pre-synaptic netrin-G1 and netrin-G2 diversify the complexity of vertebrate behaviors and differentially regulate post-synaptic properties. Our findings constitute the first genetic analysis of the behavioral and synaptic diversification roles of a vertebrate GPI protein and presynaptic adhesion molecule family.
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. zhangqi@brain.riken.jp.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. gotohiromichi@brain.riken.jp.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Goto
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. sachiko.akiyoshi@gen.mpg.de.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akiyoshi-Nishimura
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. prosselkov@brain.riken.jp.
authors.forename: Pavel
authors.initials: P
authors.lastname: Prosselkov
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. sano@brain.riken.jp.
authors.forename: Chie
authors.initials: C
authors.lastname: Sano
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. mtkwh40bg@brain.riken.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsukawa
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. yaguchi0401@gmail.com.
authors.forename: Kunio
authors.initials: K
authors.lastname: Yaguchi
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. nakashib@brain.riken.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakashiba
authors.affiliation: Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. sitohara@brain.riken.jp.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
mesh_terms: D000818:Animals; D001288:Attention; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004644:Emotions; D051528:Guanylate Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000075385:Netrins; D010641:Phenotype; D017729:Presynaptic Terminals / Q000378:metabolism*; D066191:Sensorimotor Cortex / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000075385:Netrins; C456263:Ntng2 protein, mouse; C413653:netrin-G1; D051528:Guanylate Kinases