Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice

Tomonori Kaifu, Jin Nakahara, Masanori Inui, Kenichi Mishima, Toshihiko Momiyama, Mitsuji Kaji, Akiko Sugahara, Hisami Koito, Azusa Ujike-Asai, Akira Nakamura, Kiyoshi Kanazawa, Kyoko Tan-Takeuchi, Katsunori Iwasaki, Wayne M. Yokoyama, Akira Kudo, Michihiro Fujiwara, Hiroaki Asou, Toshiyuki Takai

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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.

Original languageEnglish
Pages (from-to)323-332
Number of pages10
JournalJournal of Clinical Investigation
Volume111
Issue number3
DOIs
Publication statusPublished - 2003 Feb

ASJC Scopus subject areas

  • Medicine(all)

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    Kaifu, T., Nakahara, J., Inui, M., Mishima, K., Momiyama, T., Kaji, M., Sugahara, A., Koito, H., Ujike-Asai, A., Nakamura, A., Kanazawa, K., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W. M., Kudo, A., Fujiwara, M., Asou, H., & Takai, T. (2003). Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. Journal of Clinical Investigation, 111(3), 323-332. https://doi.org/10.1172/JCI16923