Complete Loss of <i>Fas Ligand</i> Gene Causes Massive Lymphoproliferation and Early Death, Indicating a Residual Activity of <i>gld</i> Allele

Karray, Saoussen; Kress, Chantal; Cuvellier, Sylvain; Hue-Beauvais, Catherine; Damotte, Diane; Babinet, Charles; Lévi‐Strauss, Matthieu

doi:10.4049/jimmunol.172.4.2118

Cited by 66 publications

(70 citation statements)

References 35 publications

(33 reference statements)

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“…To evaluate whether FASL expression in the osteoblast lineage cells has any effect on the maintenance of bone mass in vivo, we generated osteoblast progenitor/ osteoblast-specific FASL-deficient mice (FASL cKO) by crossing animals bearing conditional FASL knockout alleles (FASL fl/fl ) 25,26 to transgenic mice expressing Cre recombinase gene under the SP7 promoter (B6.Cg-Tg(Sp7-tTA,tetO-EGFP/cre)1Amc/J), 27 in which the Cre is inserted into the FASl locus and specifically expressed in the osteoblastic lineage (Supplementary Figure 1A). The FASL cKO mice were born alive and at predicted Mendelian frequencies, with no apparent skeletal morphological abnormalities at birth (Supplementary Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass

et al. 2015

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The interplay between osteoblasts and osteoclasts has a crucial role in maintaining bone homeostasis. In this study, we reveal that osteoblasts are capable of inducing osteoclast apoptosis by FAS ligand (FASL)/FAS signaling. Conditional knockout of FASL in osteoblasts results in elevated osteoclast numbers and activity, along with reduced bone mass, suggesting that osteoblastproduced FASL is required to maintain physiological bone mass. More interestingly, we show that osteoblasts from ovariectomized (OVX) osteoporotic mice exhibit decreased FASL expression that results from the IFN-γ-and TNF-α-activated NF-κB pathway, leading to reduced osteoclast apoptosis and increased bone resorption. Systemic administration of either IFN-γ or TNF-α ameliorates the osteoporotic phenotype in OVX mice and rescues FASL expression in osteoblasts. In addition, ovariectomy induces more significant bone loss in FASL conditional knockout mice than in control group with increased osteoclast activity in which the levels of RANKL and OPG remain unchanged. Taken together, this study suggests that osteoblast-induced osteoclast apoptosis via FASL/FAS signaling is a previously unrecognized mechanism that has an important role in the maintenance of bone mass in both physiological conditions and OVX osteoporosis.

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Section: Resultsmentioning

confidence: 99%

Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass

et al. 2015

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“…30; C.R. and B.P., unpublished data), and gld mice bear a point mutation in FasL that does not completely inactivate the ligand (31). It will thus be critical to test the effects of complete inactivation of Fas or FasL on pathological motoneuron death.…”

Section: Discussionmentioning

confidence: 99%

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Raoul

Buhler

Sadeghi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

100

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The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1 G93A and SOD1 G85R , but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas͞NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1 G93A and SOD1 G85R mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas͞NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.cell death ͉ motoneuron disease ͉ NO ͉ p38 kinase ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is the most frequent adultonset motoneuron disease in humans. ALS is characterized by the selective degeneration of motoneurons in spinal cord, brainstem, and cerebral cortex leading to muscle atrophy and paralysis and ultimately to death. About 1 to 2% of all human ALS forms are caused by dominantly inherited mutations in the Cu͞Zn superoxide dismutase (SOD1) gene. Mice transgenic for the ALS-linked SOD1 mutations G37R (1), H46R͞H48Q (2), G85R (3), and G93A (4) develop an adult-onset motoneuron disorder that remarkably resembles human ALS.Despite much intensive study, many questions remain concerning the mechanism(s) by which mutant SOD1 triggers specific motoneuron death. One unresolved issue is the cellular site of action of the gain-of-function mutations. Clement et al. (5) generated chimeric mice carrying a mixture of WT and mutant SOD1-expressing cells in the spinal cord. In these mice, WT motoneurons eventually showed stigmata of degeneration, whereas some mutant SOD1 motoneurons were protected from degeneration when surrounded by WT nonneuronal cells. These results suggest that mutant SOD1 in both motoneurons and surrounding cells may play a role in the disease process.Our earlier studies using cultures of purified embryonic motoneurons reached similar conclusions. We found that motoneurons from SOD1 G93A , SOD1 G37R , and SOD1 G85R mice survived normally in the presence of optimal trophic support or when challenged by excitotoxic agonists. In marked contrast, compared with controls, they displayed a 10-to 100-fold increase in sensitivity to extracellular agonists of the Fas receptor or to exogenous nitr...

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“…14 Moreover, mice deficient for FasL or Apo2L/TRAIL signaling complete embryogenesis without significant defects. [15][16][17][18] To gain further insight into the evolution of the extrinsic apoptosis pathway and its importance during embryogenesis, we turned to the zebrafish (Danio rerio). Although known zebrafish expressed sequence tags (ESTs) appear to encode portions of apoptosis genes, 19 the extrinsic pathway remains poorly understood in this model organism.…”

Section: Introductionmentioning

confidence: 99%

Delineation of the cell-extrinsic apoptosis pathway in the zebrafish

et al. 2006

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The mammalian extrinsic apoptosis pathway is triggered by Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL). Ligand binding to cognate receptors activates initiator caspases directly in a death-inducing signaling complex. In Drosophila, TNF ligand binding activates initiator caspases indirectly, through JNK. We characterized the extrinsic pathway in zebrafish to determine how it operates in a nonmammalian vertebrate. We identified homologs of FasL and Apo2L/TRAIL, their receptors, and other components of the cell death machinery. Studies with three Apo2L/TRAIL homologs demonstrated that they bind the receptors zHDR (previously linked to hematopoiesis) and ovarian TNFR (zOTR). Ectopic expression of these ligands during embryogenesis induced apoptosis in erythroblasts and notochord cells. Inhibition of zHDR, zOTR, the adaptor zFADD, or caspase-8-like proteases blocked ligand-induced apoptosis, as did antiapoptotic Bcl-2 family members. Thus, the extrinsic apoptosis pathway in zebrafish closely resembles its mammalian counterpart and cooperates with the intrinsic pathway to trigger tissue-specific apoptosis during embryogenesis in response to ectopic Apo2L/TRAIL expression.

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Complete Loss of Fas Ligand Gene Causes Massive Lymphoproliferation and Early Death, Indicating a Residual Activity of gld Allele

Cited by 66 publications

References 35 publications

Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass

Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL

Delineation of the cell-extrinsic apoptosis pathway in the zebrafish

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