title: Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages.
abstract: Human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease, has been described to be associated with mutations affecting the immunoreceptor tyrosine-based activation motif-bearing KARAP/DAP12 immunoreceptor gene. Patients present bone fragilities and severe neurological alterations leading to presenile dementia. Here we investigated whether the absence of KARAP/DAP12-mediated signals in loss-of-function (KDelta75) mice also leads to bone and central nervous system pathological features. Histological analysis of adult KDelta75 mice brains revealed a diffuse hypomyelination predominating in anterior brain regions. As this was not accompanied by oligodendrocyte degeneration or microglial cell activation it suggests a developmental defect of myelin formation. Interestingly, in postnatal KDelta75 mice, we observed a dramatic reduction in microglial cell numbers similar to in vitro microglial cell differentiation impairment. Our results raise the intriguing possibility that defective microglial cell differentiation might be responsible for abnormal myelin development. Histomorphometry revealed that bone remodeling is also altered, because of a resorption defect, associated with a severe block of in vitro osteoclast differentiation. In addition, we show that, among monocytic lineages, KARAP/DAP12 specifically controls microglial and osteoclast differentiation. Our results confirm that KARAP/DAP12-mediated signals play an important role in the regulation of both brain and bone homeostasis. Yet, important differences exist between the symptoms observed in Nasu-Hakola patients and KDelta75 mice.
authors.affiliation: INSERM U433, Faculté Laennec, Lyon, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Nataf
authors.forename: Adrienne
authors.initials: A
authors.lastname: Anginot
authors.forename: Carine
authors.initials: C
authors.lastname: Vuaillat
authors.forename: Luc
authors.initials: L
authors.lastname: Malaval
authors.forename: Nassima
authors.initials: N
authors.lastname: Fodil
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chereul
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Langlois
authors.forename: Christiane
authors.initials: C
authors.lastname: Dumontel
authors.forename: Gaelle
authors.initials: G
authors.lastname: Cavillon
authors.forename: Christian
authors.initials: C
authors.lastname: Confavreux
authors.forename: Marlène
authors.initials: M
authors.lastname: Mazzorana
authors.forename: Laurence
authors.initials: L
authors.lastname: Vico
authors.forename: Marie-Franaçoise
authors.initials: MF
authors.lastname: Belin
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Elena
authors.initials: E
authors.lastname: Tomasello
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001847:Bone Diseases / Q000235:genetics* / Q000473:pathology; D001925:Brain Damage, Chronic / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011971:Receptors, Immunologic; C484963:Tyrobp protein, mouse