Neonatal mice lacking functional Fas death receptors are resistant to hypoxic-ischemic brain injury.
Neonatal hypoxia-ischemia (HI) upregulates Fas death receptor expression in the brain, and alterations in expression and activity of Fas signaling intermediates occur in neonatal brain injury. B6.MRL-Tnfrsf6(lpr) mice lacking functional Fas death receptors are protected from HI brain damage in cortex, striatum, and thalamus compared to wild-type mice. Expression of Fas death receptor and active caspases increase in the cortex after HI. In wild-type mice, the hippocampus is most severely injured, and the hippocampus is the only region not protected in the B6.MRL-Tnfrsf6(lpr) mice. The selective vulnerability of the hippocampus to injury correlates with (1) lower basal expression of [Fas-associated death-domain-like IL-1beta-converting enzyme]-inhibitory protein (FLIP), (2) increased degradation of spectrin to its 145 or 150 kDa breakdown product, and (3) a higher percentage of non-apoptotic cell death following neonatal HI. We conclude that Fas signaling via both extrinsic and intrinsic caspase cascades causes brain injury following neonatal HI in a region-dependent manner. Basal levels of endogenous decoy proteins may modulate the response to Fas death receptor signaling and provide a novel approach to understanding mechanisms of neonatal brain injury.
Graham
Ernest M
EM
Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sheldon
R Ann
RA
Flock
Debra L
DL
Ferriero
Donna M
DM
Martin
Lee J
LJ
O'Riordan
Declan P
DP
Northington
Frances J
FJ
D000818:Animals; D000831:Animals, Newborn / Q000235:genetics*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
D019014:fas Receptor