Developmental regulation of TREM2 and DAP12 expression in the murine CNS: implications for Nasu-Hakola disease.
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.
Thrash
J Cameron
JC
Division of Biomedical Sciences, Center for Glial-Neuronal Interactions, University of California Riverside, 900 University Ave, Riverside, CA, 92521, USA.
Torbett
Bruce E
BE
Carson
Monica J
MJ
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D001847:Bone Diseases / Q000235:genetics; D002490:Central Nervous System / Q000254:growth & development* / Q000378:metabolism; D015140:Dementia, Vascular / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D015398:Signal Transduction / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; C484963:Tyrobp protein, mouse