Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Dap12-deficient mouse brain (1 month)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Anna Kiialainen

PROVIDER: E-GEOD-9061 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Nasu-Hakola disease (NHD), also designated polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare autosomal recessive disorder characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by a loss-of-function mutation of DAP12 or TREM2. TREM2 and DAP12 constitute a receptor/adaptor complex expressed on osteoclasts, dendritic cells, macrophages, monocytes, and microglia. At present, the precise molecular mechanisms underlying development of leukoencephalopathy and bone cysts in NHD remain largely unknown. We established THP-1 human monocyte clones that stably express small interfering RNA (siRNA) targeting DAP12 for serving as a cellular model of NHD. Genome-wide transcriptome analysis identified a set of 22 genes consistently downregulated in DAP12 knockdown cells. They constituted the molecular network closely related to the network defined by cell-to-cell signaling and interaction, hematological system development and function, and inflammatory response, where NF-kappaB acts as a central regulator. These results suggest that a molecular defect of DAP12 in human monocytes deregulates the gene network pivotal for maintenance of myeloid cell function in NHD. We found that both DAP12 knockdown and control clones were capable of equally responding to phorbol 12-myristate 13-acetate (PMA), a known inducer of morphological differentiation of THP-1 cells, by exhibiting almost similar gene expression profiles between both, following a 24-hour exposure to 50 nM PMA. The siRNA vector construct targeting the DAP12 sequence (SI) and the control vector construct targeting the scrambled sequence (SCR) were generated by using GeneClip U1 Hairpin cloning system (Promega). The vectors were transfected in THP-1 cells by using Lipofectamine LTX reagent. The stable cell lines were selected by incubating them for approximately two months in the feeding medium with inclusion of 200 microgram/ml Hygromycin B. Then, two SI clones named SI5 and SI17, in addition to two SCR clones named SCR1 and SCR4, were selected by limiting dilution of the cells in a manner of a single cell per well plated in a 96-well cell culture plate. Microarray data for clones SCR4 and SI17 submitted in this Series.

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Dap12-deficient mouse brain (1 month)

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