title: Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene.
abstract: Sexual differentiation of the brain in rodents is achieved by estrogens, which are converted from androgens in the brain, during the perinatal period. We have identified the progranulin (PGRN) gene as one of the sex steroid-inducible genes that may be involved in masculinization of the rat brain. In the present study, we generated a line of mice with targeted disruption of the PGRN gene, and investigated male sexual behaviour, aggression and anxiety. PGRN-deficient mice exhibited a decrease in ejaculation incidence, while the latency and frequency of both mount and intromission were unchanged. For the aggressive behaviour test, the resident-intruder paradigm was used, and PGRN-deficient mice exhibited enhanced aggressiveness. In wild-type mice, males exhibited lower levels of anxiety than females by the open field test, while male PGRN-deficient mice exhibited an elevated level of anxiety and sex difference in anxiety was not observed. In addition, mRNA expression of the serotonergic receptor 5-HT1A, which could be related to the inhibition of aggression and anxiety, was significantly reduced in the hippocampus of PGRN-deficient mice after aggressive encounters. On the other hand, deficiency of the PGRN gene did not affect serum testosterone concentrations. These results suggest that PGRN gene plays a role in establishing sexual dimorphic behaviours at least partially by modulating the brain serotonergic system.
authors.affiliation: Department of Veterinary Physiology, Veterinary Medical Science, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kayasuga
authors.forename: Shuichi
authors.initials: S
authors.lastname: Chiba
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kikusui
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuwaki
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamanouchi
authors.forename: Hayato
authors.initials: H
authors.lastname: Kotaki
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Masugi
authors.initials: M
authors.lastname: Nishihara
mesh_terms: D000374:Aggression / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077153:Progranulins; D012333:RNA, Messenger / Q000032:analysis; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000235:genetics / Q000502:physiology*; D012726:Sexual Behavior, Animal / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012333:RNA, Messenger; D044282:Receptor, Serotonin, 5-HT1A