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Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice
Tomonori Kaifu, … , Hiroaki Asou, Toshiyuki Takai
Tomonori Kaifu, … , Hiroaki Asou, Toshiyuki Takai
Published February 1, 2003
Citation Information: J Clin Invest. 2003;111(3):323-332. https://doi.org/10.1172/JCI16923.
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Article Neuroscience

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

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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.

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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Figure 2

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Osteopetrosis in DAP12–/– mice. (a) Micro-CT 3D images of tibial metaphy...
Osteopetrosis in DAP12–/– mice. (a) Micro-CT 3D images of tibial metaphyses of 40-week-old wild-type and DAP12–/– mice. DAP12–/– mice showed increased bone mass. (b) Hematoxylin and eosin staining of metaphysis sections from 6-week-old wild-type and mutant mice. (c) Percentages of trabecular bone volume per total tissue volume (BV/TV) of the femurs from wild-type (black bars) and mutant mice (white bars) at various ages. *P < 0.05. n = 3. (d) The numbers of TRAP+ multinucleated osteoclasts (OCs) in 6-week-old wild-type and DAP12–/– mice are not significantly different. (e) Transmission electron micrographs of in vivo osteoclasts from wild-type and DAP12–/– mice do not show significant differences. DAP12–/– osteoclasts displayed a ruffled border (rb), a complex membrane structure, which is usually associated with active bone matrix resorption, and a clear zone (cz) attached to the bone matrix.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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