Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.
Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.
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DOI：
10.1172/jci16923
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发表时间：
2003-02
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影响因子：
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通讯作者：
T. Kaifu;J. Nakahara;M. Inui;K. Mishima;T. Momiyama;Mitsuji Kaji;Akiko Sugahara;H. Koito;Azusa Ujik
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文献类型：
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作者：
T. Kaifu;J. Nakahara;M. Inui;K. Mishima;T. Momiyama;Mitsuji Kaji;Akiko Sugahara;H. Koito;Azusa Ujik
人类DAP12基因缺失导致Nasu-Hakola病，其特征是骨折和类似精神分裂症的精神病症状的组合，迅速发展为老年痴呆。然而，尚不清楚为什么这些疾病是由于DAP12缺乏而发展的，DAP12是一种免疫受体信号激活蛋白，最初在免疫系统中被发现。在这里，我们发现DAP12缺陷（DAP12(-/-)）小鼠的骨量增加（骨质疏松症），髓磷脂减少（低髓磷脂症）在丘脑中加剧。DAP12（-/-）骨髓细胞体外诱导破骨细胞产生骨吸收活性减弱的未成熟细胞。此外，未成熟的少突胶质细胞在丘脑附近被阻滞，这表明DAP12（-/-）小鼠的主要缺陷是破骨细胞和少突胶质细胞的发育阻滞。此外，突变小鼠还表现出突触变性，脉冲前抑制受损，这在包括精神分裂症在内的几种人类神经精神疾病中常见，并且丘脑电生理谱异常。这些结果为Nasu-Hakola病以及精神分裂症和老年痴呆的骨骼和精神病特征的独特组合提供了分子基础。
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.