Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice

Abstract

Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12–/–) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12–/– bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligodendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12–/– mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia

Siglec-15 Regulates Osteoclast Differentiation by Modulating RANKL-Induced Phosphatidylinositol 3-Kinase/Akt and Erk Pathways in Association With Signaling Adaptor DAP12

“…Osteoclasts are differentiated from hematopoietic precursors of the monocyte/macrophage lineage by stimulation with a tumor necrosis factor family cytokine, receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF). Because these two cytokines induce osteoclasts in vitro, they were thought to be sufficient for osteoclastogenesis, but recent studies demonstrated that osteoclastogenesis also requires immunoreceptor tyrosine‐based activation motif (ITAM) signaling …”

PLCγ2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2

“…The 2 ITAMcontaining adapters, Dap12 and the γ chain of Fc receptor (FcRγ), have a profound impact on OCs by modulating RANKL-mediated calcium influx and NFATc1 expression. In humans, mutation in the Dap12 gene is responsible for Nasu-Hakola disease, characterized by multiple bone cysts associated with a unique form of neurodegeneration (21). Deletion of Dap12 and FcRγ (Dap12 -/-FcRγ -/-), in mice, leads to severe osteopetrosis due to defective OC development (20)(21)(22).…”

“…In humans, mutation in the Dap12 gene is responsible for Nasu-Hakola disease, characterized by multiple bone cysts associated with a unique form of neurodegeneration (21). Deletion of Dap12 and FcRγ (Dap12 -/-FcRγ -/-), in mice, leads to severe osteopetrosis due to defective OC development (20)(21)(22). In vitro triggering of either receptor by crosslinking with an antibody accelerates RANKL-induced OC differentiation (23).…”

DAP12 signaling: from immune cells to bone modeling and brain myelination

“…Takai and colleagues also demonstrate that DAP12 is expressed in normal oligodendrocytes and microglial cells (3). Oligodendrocytes form the myelin sheath that wraps around neural axons, enhancing nerve signal conductance in the CNS and ensuring axonal integrity.…”

“…The study by Takai et al shows that DAP12 protein is expressed in normal osteoclasts (3). These are polykarions of the monocyte/macrophage lineage that specialize in bone resorption (9).…”