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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Expression of DAP12 in oligodendrocytes, and ectopic oligodendrocytes in...
Expression of DAP12 in oligodendrocytes, and ectopic oligodendrocytes in DAP12–/– mice. (a) RT-PCR analysis for DAP12 mRNA in oligodendrocyte progenitor cells (A2B5+, O4+, or O1+ cells) and microglial cells prepared from wild-type mice. LAK cells from wild-type mice presented as a positive control. Oligodendrocyte precursor cells are positive for mRNA of DAP12 as well as proteolipid protein (PLP) and its splice variant, DM20, marker proteins for oligodendrocytes. (b) Northern blot analysis of DAP12 mRNA in neuron, astrocyte, oligodendrocyte, and microglia. Thirty micrograms (neuron, astrocyte, and oligodendrocyte) or 5 μg (microglia) of total RNA was subjected to electrophoresis on a 1.2% agarose gel containing formaldehyde, transferred to nylon membrane, and probed with [α-32P]dCTP–labeled, full-length coding region of DAP12 cDNA. Oligodendrocytes and microglia expressed a significant amount of DAP12 mRNA. (c) Immunoblot analysis of DAP12. Oligodendrocytes and microglia express DAP12 protein, although the expression levels were less significant than those in LAK cells. (d) Staining for MBP of the internal capsule (ic) and thalamus (thlm) from 3-month-old DAP12–/– (upper left and lower) and wild-type (upper right) mice. Ectopic, MBP-positive oligodendrocyte clusters were observed in DAP12–/– mice. Scale bars, 100 μm.