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 1

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Targeted mutation of the DAP12 gene in mice. (a) Schematic illustration ...
Targeted mutation of the DAP12 gene in mice. (a) Schematic illustration of the DAP12 locus (top), targeting vector (middle), and disrupted allele (bottom). Exons 1–5 (I–V) are shown (filled boxes). Exon 4 of the DAP10 gene is also shown (open box). The neor (neo) and thymidine kinase (TK) genes and the probe (shaded box) for Southern blotting are shown. A 5.1-kb BamHI fragment containing the promoter region and exons 1–3 of the DAP12 gene was replaced by a neor cassette; 5.1 kb and 1.2 kb of homologous sequences flanking the neor cassette were retained. (b) Southern blot analysis to confirm the genotype of DAP12 wild-type (+/+), heterozygote (+/–), and knockout (–/–) offspring. Genomic DNA isolated from the tail tips of offspring of heterozygous intercrosses were digested with KpnI and probed. The wild-type allele migrates as a 6.0-kb fragment; the disrupted allele, 4.8 kb. (c) Immunoblot analysis. Protein extracts from IL-2–induced LAK cells (5 × 105 cell equivalent per lane) of wild-type or DAP12–/– mice were probed with rabbit anti-DAP12 antiserum (1:1,000 dilution) or β-actin antibody. DAP12 protein was not detected in the cells from DAP12–/– mice.