Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease
- 595 Downloads
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.
KeywordsTREM PLOSL Neuroinflammation Myelin Neurodegeneration
MJC was supported by NIH grants NS045735, NS39508 and a PIC grant from the Division of Biomedical Sciences, University of California Riverside.
- 2.Bianchin MM, Capella HM, Chaves DL, Steindel M, Grisard EC, Ganev GG, da Silva Junior JP, Neto Evaldo S, Poffo MA, Walz R, Carlotti Junior CG, Sakamoto AC (2004) Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy—PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell Mol Neurobiol 24:1–24PubMedCrossRefGoogle Scholar
- 4.Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71:656–662PubMedCrossRefGoogle Scholar
- 10.Prada I, Ongania GN, Buonsanti C, Panina-Bordignon P, Meldolesi J (2006) Triggering receptor expressed in myeloid cells 2 (TREM2) trafficking in microglial cells: continuous shuttling to and from the plasma membrane regulated by cell stimulation. Neuroscience 140:1139–1148PubMedCrossRefGoogle Scholar
- 20.Kaifu T, Nakahara J, Inui M, Mishima K, Momiyama T, Kaji M, Sugahara A, Koito H, Ujike-Asai A, Nakamura A, Kanazawa K, Tan-Takeuchi K, Iwasaki K, Yokoyama WM, Kudo A, Fujiwara M, Asou H, Takai T (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111:323–332PubMedGoogle Scholar
- 22.Nataf S, Anginot A, Vuaillat C, Malaval L, Fodil N, Chereul E, Langlois JB, Dumontel C, Cavillon G, Confavreux C, Mazzorana M, Vico L, Belin MF, Vivier E, Tomasello E, Jurdic P (2005) Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages. Am J Pathol 166:275–286PubMedGoogle Scholar
- 23.Kiialainen A, Veckman V, Saharinen J, Paloneva J, Gentile M, Hakola P, Hemelsoet D, Ridha B, Kopra O, Julkunen I, Peltonen L (2007) Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response. J Mol Med 85:971–983PubMedCrossRefGoogle Scholar
- 27.Thomas EA, George RC, Danielson PE, Nelson PA, Warren AJ, Lo D, Sutcliffe JG (2003) Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins. Mol Psychiatry 8:983–993, 950Google Scholar