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

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 4

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Thalamus-accentuated hypomyelinosis in DAP12–/– mice. (a) Thalamus-accen...
Thalamus-accentuated hypomyelinosis in DAP12–/– mice. (a) Thalamus-accentuated reduction of MBP staining. Coronal brain sections were stained with anti-MBP antibody. The left side is from DAP12–/– mouse and the right side is from wild-type mouse, both at 3 months of age. Each panel is composed of multiple pictures. Arrow indicates the thalamus-accentuated reduction of MBP staining. fm, fimbria; ic, internal capsule; ptm, putamen; thlm, thalamus. Scale bar, 250 μm. (b–e) Ultrastructure of medial thalamus (b–d) and putamen (e). (b) Lower-magnification views (original magnification: ×2,000) of medial thalamus of 6-month-old DAP12–/– and wild-type mice. Myelinated axons are reduced significantly in the DAP12–/– mouse, while blood vessels appear to be normal (arrow). (c and d) Higher-magnification views (×10,000 for c, ×50,000 for d) showing many unmyelinated axons with aberrant morphology (arrows) and electron-dense appearance of the non-axonal area (c), and synaptic degeneration and abnormal accumulation of synaptic vesicles (flanked by arrowheads) in the DAP12–/– mouse (d). (e) Putamen of 3-month-old mice. Hypomyelinosis is not evident in this area, but a somewhat distorted axon shape is evident. Original magnification: ×40,000. Scale bar, 250 nm.