title: Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia.
abstract: Together with its adaptor protein, the adaptor protein of 12 kDa also known as KARAP and TYROBP (DAP12), triggering receptor expressed in myeloid cells 2 (TREM2) is a stimulatory membrane receptor of the immunoglobulin/lectin-like superfamily, well known in myeloid cells. In humans, however, loss-of-function mutations of TREM2/DAP12 leave myeloid cells unaffected but induce an autosomal recessive disease characterized, together with bone cysts, by a spectrum of pathological lesions in the cortex, thalamus and basal ganglia with clinical symptoms of progressive dementia (polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy). Nothing was known about the role of TREM2/DAP12 in brain cell biology and physiology. By confocal immunocytochemistry we demonstrate that, in both human and mouse cerebral cortex, TREM2/DAP12, strongly expressed by microglia, is also present in a fraction of neurons but not in astrocytes and oligodendrocytes. In contrast, in the hippocampal cortex TREM2-expressing neurons are rare. Both in neurons and microglia the receptor appears to be located mostly intracellularly in a discrete compartment(s) partially coinciding with (or adjacent to) the Golgi complex/trans-Golgi network. Four nerve cell lines were identified as expressing the intracellular receptor system. In living human microglia CHME-5 and glioblastoma T98G cells, activation of TREM2 by its specific antibody induced [Ca2+]i responses, documenting its surface expression and functioning. Surface expression of TREM2, low in resting CHME-5 and T98G cells, increases significantly and transiently (60 min) when cells are stimulated by ionomycin, as revealed by both surface biotinylation and surface immunolabeling. Our results provide the first information about the expression, distribution (mostly intracellular) and functioning of TREM2/DAP12 system in nerve cells, a necessary step in the understanding of the cellular mechanisms affected in polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy.
authors.affiliation: Department of Neuroscience, DIBIT, Vita-Salute San Raffaele University and San Raffaele Institute, Via Olgettina 58, 20132 Milan, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Sessa
authors.forename: Paola
authors.initials: P
authors.lastname: Podini
authors.forename: Margherita
authors.initials: M
authors.lastname: Mariani
authors.forename: Alessandra
authors.initials: A
authors.lastname: Meroni
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.forename: Francesco
authors.initials: F
authors.lastname: Sinigaglia
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Paola
authors.initials: P
authors.lastname: Panina
authors.forename: Jacopo
authors.initials: J
authors.lastname: Meldolesi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D003704:Dementia / Q000150:complications / Q000235:genetics; D004347:Drug Interactions; D004827:Epilepsy / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D000077614:Golgi Matrix Proteins; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D022423:Myeloid Cells / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013344:Subacute Sclerosing Panencephalitis / Q000150:complications / Q000235:genetics; D013997:Time Factors; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D005904:Glial Fibrillary Acidic Protein; D000077614:Golgi Matrix Proteins; D007476:Ionophores; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C498715:TREM2 protein, human; C110546:TYROBP protein, human; C498716:Trem2 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C484963:Tyrobp protein, mouse; C087574:macrogolgin; D015759:Ionomycin; D010751:Phosphopyruvate Hydratase; D002118:Calcium