Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease
Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease
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DOI：
10.1007/s11064-008-9657-1
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发表时间：
2009-01-01
影响因子：
4.4
通讯作者：
Carson, Monica J.
中科院分区：
文献类型：
--
作者：
Thrash, J. Cameron;Torbett, Bruce E.;Carson, Monica J.
Trem 2是一种孤儿，DAP 12相关受体，在健康成年鼠CNS中由小胶质细胞亚群在体内组成型表达，在新生儿混合胶质细胞培养物中由少突胶质细胞亚群在体外组成型表达。功能性Trem 2信号通路的缺失是Nasu-Hakola病的遗传原因。与这种疾病相关的早发性认知痴呆和髓鞘苍白是否是由于小胶质细胞和/或少突胶质细胞中功能性Trem 2信号传导的缺陷仍有争议。在这里，我们发现，Trem 2/DAP 12的表达检测胚胎14天的CNS mRNA。使用双重免疫组织化学/原位杂交，我们发现Trem 2和DAP 12的表达总是与小胶质细胞/巨噬细胞的标志物共定位。然而，在髓鞘形成之前（出生后第1天），Trem 2/DAP 12阳性小胶质细胞与CNP+少突胶质细胞非常接近并置。此外，在缺乏小胶质细胞和巨噬细胞的PU.1KO中未检测到TREM 2和DAP 12的CNS表达。我们的数据为Nasu-Hakola病被确定为由CNS小胶质细胞原发性功能障碍引起的认知障碍提供了持续支持。
Trem2 is an orphan, DAP12 associated receptor constitutively expressed in vivo by subsets of microglia in the healthy adult murine CNS and in vitro by subsets of oligodendrocytes in neonatal mixed glial cultures. Loss of a functional Trem2 signaling pathway is the genetic cause of Nasu-Hakola disease. Whether the early onset cognitive dementia and myelin-pallor associated with this disorder are due to deficits in functional Trem2 signaling in microglia and/or oligodendrocytes is still being debated. Here, we find that Trem2/DAP12 expression is detected in embryonic day 14 CNS mRNA. Using dual immunohistochemistry/in situ hybridization, we find that both Trem2 and DAP12 expression always co-localized with markers of microglia/macrophages. However, Trem2/DAP12 positive microglia are found in very close apposition with CNP+ oligodendrocytes prior to myelination (post-natal day 1). In addition, CNS expression of TREM2 and DAP12 are not detected in PU.1KO which lack microglia and macrophages. Our data provide continuing support for Nasu-Hakola disease being identified as a cognitive disorder caused by a primary dysfunction of CNS microglia.