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.

CSF-1 Receptor Signaling in Myeloid Cells

“…The response is enhanced by DAP12-independent CSF-1R inhibition of b-catenin degradation (Otero et al 2009). DAP12 deficiency leads to impaired CSF-1R-mediated proliferation and survival, but does not affect differentiation (Nataf et al 2005;Otero et al 2009). …”

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

“…Osteoclasts derive from hematopoietic precursors of the monocytic lineage and express high levels of KARAP/ DAP12 and TREM-2 transcripts [47]. In vitro osteoclast differentiation is dramatically affected in both TREM-2-and KARAP/DAP12-deficient PLOSL patients as well as in KARAP/DAP12-deficient mice [49][50][51]. Osteoclasts are present in vivo, although their function seems to be compromised, as indicated by alteration of bone density in both patients and mutant mice.…”

“…Hypomyelination has also been detected in brains of KARAP/DAP12-deficient mice, although without any sign of inflammation [50,51]. The KARAP/DAP12-dependent mechanisms responsible for this brain pathology are still unknown.…”

“…The KARAP/DAP12-dependent mechanisms responsible for this brain pathology are still unknown. KARAP/DAP12 expression is detectable in human and mouse brain, in particular in microglial cells [46,51,53]. Controversial data have been published regarding KARAP/DAP12 expression in in-vitro-cultured oligodendrocytes, cells primarily involved in the production of myelin sheath [50,51,53].…”

Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease

“…First, histological analysis of adult CNS tissue from DAP12 knock-out mice in studies by two separate groups revealed modest, diffuse hypomyelination in anterior brain regions that was associated with substantial reductions in CNS microglia [20][21][22]. Subsequent gene profiling studies of CNS mRNA isolated from DAP12KO mice by a third group revealed decreased expression of selected myelin transcripts [23].…”