Dap12-deficient mouse brain (1 month)

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is an inherited brain and bone disease. It manifests as dementia and bone fractures. The PLOSL phenotype is caused by loss-of-function mutations in one of the two genes encoding the components of the DAP12/TREM2 receptor complex. The DAP12/TREM2 complex is expressed in cells of the myeloid lineage, including microglia in the central nervous system (CNS). The molecular mechanisms producing the CNS phenotype of PLOSL remain largely unknown. To gain insight into dysfunctional CNS pathways behind PLOSL, we performed genome-wide expression analysis of Dap12 (Tyrobp)-deficient mouse brain. In Dap12-deficient mice, we observed alterations in several pathways involved in synaptic function. In agreement with the myelin loss in PLOSL patients, we also saw changes in transcript levels of genes encoding myelin components. Keywords: knockout response Transcript profiles of the midbrain (diencephalon and basal ganglia) of three Dap12-knockout and three heterozygous mice were analyzed.硬化性脑白质病伴多囊脂膜性骨发育不良（Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy，PLOSL）是一种遗传性脑骨共患病。该病以痴呆与骨折为主要临床表现。PLOSL的表型由编码DAP12/TREM2受体复合物组分的两个基因之一发生功能丧失性突变所导致。DAP12/TREM2复合物表达于髓系细胞谱系，包括中枢神经系统（Central Nervous System，CNS）中的小胶质细胞（microglia）。目前，PLOSL中枢神经系统表型的分子机制仍未得到充分阐明。为深入解析PLOSL背后的中枢神经系统功能异常通路，我们对Dap12（Tyrobp）缺陷型小鼠的大脑开展了全基因组表达分析。在Dap12缺陷型小鼠中，我们观察到多条参与突触功能调控的通路发生异常改变。与PLOSL患者的髓鞘丢失表型相一致，我们还发现髓鞘组分编码基因的转录水平存在显著变化。关键词：敲除应答。本研究对3只Dap12敲除型小鼠与3只杂合子小鼠的中脑（间脑与基底神经节）转录谱进行了分析。