title: Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.
abstract: Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12(-/-)) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12(-/-) bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligodendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12(-/-) mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia.
authors.affiliation: Department of Experimental Immunology and Core Research for Evolutional Science and Technology (CREST) Program of the Japan Science and Technology Corporation (JST), Tohoku University, Sendai, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kaifu
authors.forename: Jin
authors.initials: J
authors.lastname: Nakahara
authors.forename: Masanori
authors.initials: M
authors.lastname: Inui
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Momiyama
authors.forename: Mitsuji
authors.initials: M
authors.lastname: Kaji
authors.forename: Akiko
authors.initials: A
authors.lastname: Sugahara
authors.forename: Hisami
authors.initials: H
authors.lastname: Koito
authors.forename: Azusa
authors.initials: A
authors.lastname: Ujike-Asai
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kanazawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tan-Takeuchi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: Akira
authors.initials: A
authors.lastname: Kudo
authors.forename: Michihiro
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asou
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
mesh_terms: D000483:Alleles; D000818:Animals; D001862:Bone Resorption / Q000235:genetics; D002478:Cells, Cultured; D004594:Electrophysiology; D018390:Gene Targeting; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D010010:Osteoclasts / Q000378:metabolism; D010022:Osteopetrosis / Q000235:genetics*; D018079:Receptors, GABA / Q000378:metabolism; D013216:Reflex, Startle; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000378:metabolism*; D013788:Thalamus / Q000473:pathology; D013997:Time Factors
chemical_list: D018079:Receptors, GABA