No 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.

The present study sought to validate the use of glycery1-2-oley-1,3-bis-[7-(3-amino-2,4,6-triiodophenyl)- heptanoate] (DHOG) contrast agent for mouse spleen tumor and liver metastasis imaging by high-resolution X-ray microtomography. Three groups of female nude mice were compared: controls (n = 5), and mice injected with 2.5 x 10(6) STC1 tumor cells in the spleen, imaged at 15 days (group G15, n = 5) and at 30 days (group G30, n = 5, of which one died before imaging). Micro-CT scans (X-ray voltage, 50 kVp; anode current, 200 microA; exposure time, 632 ms; 180 rotational steps resulting in 35 microm isotropic spatial resolution) were acquired at 0, 0.75, 2 and 4 h after i.v. injection of DHOG. CT number (Hounsfield units: HU) and contrast-to-noise ratios (CNR) were determined in three organs. Statistical analysis was performed by Mann-Whitney U-test. Contrast enhancement in normal spleen and liver increased, respectively to 1020 +/- 159 and 351 +/- 27 HU over baseline at 4 h, and 482 +/- 3 and 203 +/- 14 HU on day 6 after a single contrast injection. Automated three-dimensional reconstruction and modeling of the spleen provided accurate and quantifiable images. Spleen tumor and liver metastases did not take up DHOG, making them detectable in contrast to the increased signal in normal tissue. The smallest liver metastasis detected measured 0.3 mm in diameter. High-resolution X-ray micro-CT in living mice using DHOG contrast agent allowed visualization and volume quantification of normal spleen and of spleen tumor and its liver metastases.

Clinical magnetic resonance imaging (MRI) offers a noninvasive diagnostic tool for neurodegenerative diseases. MRI was performed on mice to investigate a relationship between brain atrophy and overexpression of two genes involved in such diseases, SOD1 (superoxide dismutase) and APP (amyloid precursor protein), which have been associated with pathogenesis of Alzheimer's disease or Down syndrome. Additionaly, we investigated how life span and growth rate were affected by genetic background. T2-weighted MRI made possible the measurement of the volume of brain regions of interest in living transgenic mice that overexpress normal APP, SOD1, or both. The most pronounced alterations in gray matter volume were observed in 1-year-old double APP/SOD1 transgenic mice. Hippocampus, entorhinal, and cingulate cortex volumes were decreased by 8% to 25%. In contrast, mice homozygous for SOD1 exhibited atrophy specifically in cortex regions (cingulate, retrosplenial, and temporoparietal cortex), but no significant modification was found in the hippocampus region. None of these alterations was seen in single APP transgenics. However, the life span of these mice was significantly shortened. SOD1 overexpression prevented APP toxicity with regard to premature death, especially in double APP/SOD1 transgenic animals homozygous for SOD1, and increase in life span was significantly correlated to SOD1 activity. In conclusion, overexpression of both APP and SOD1, in contrast to single APP transgenics, produced a robust effect on brain anatomy but did not impair growth or life span. Consequences of genotype alterations on brain atrophy may be dissociated from their effect on life span.