Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.
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.
Kaifu
Tomonori
T
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.
Nakahara
Jin
J
Inui
Masanori
M
Mishima
Kenichi
K
Momiyama
Toshihiko
T
Kaji
Mitsuji
M
Sugahara
Akiko
A
Koito
Hisami
H
Ujike-Asai
Azusa
A
Nakamura
Akira
A
Kanazawa
Kiyoshi
K
Tan-Takeuchi
Kyoko
K
Iwasaki
Katsunori
K
Yokoyama
Wayne M
WM
Kudo
Akira
A
Fujiwara
Michihiro
M
Asou
Hiroaki
H
Takai
Toshiyuki
T
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
D018079:Receptors, GABA