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
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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Article Neuroscience

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

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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In vitro development of osteoclasts from DAP12–/– mice is impaired. (a) ...
In vitro development of osteoclasts from DAP12–/– mice is impaired. (a) TRAP staining of cultured osteoclasts induced in vitro in the presence of M-CSF and RANKL. Reduction of multinucleated TRAP+ osteoclasts is evident in cells from DAP12–/– mice. Original magnification: ×100. Multinucleated osteoclasts are developed from DAP12–/– bone marrow cells as seen at higher magnification (original magnification: ×400). (b) Comparison of the number of multinucleated (having more than two nuclei) TRAP+ osteoclasts induced by RANKL (left) or TNF-α (right). *P < 0.05, **P < 0.01. n = 3. (c) Actin ring formation by osteoclasts. DAP12–/– osteoclasts did not form actin rings. (d) Formation of resorption pits by osteoclasts induced in wild-type or DAP12–/– mice. DAP12–/– osteoclasts did not form significant pits. *P < 0.05. n = 3. (e) Immunoblot analysis of DAP12 expression in osteoclasts induced from bone marrow cells. Osteoclasts (10 μg protein per lane) from wild-type mice showed DAP12 expression, although at lower levels than were measured in bone marrow–derived cultured mast cells (BMMCs) (10 μg protein per lane) from wild-type mice.