Neonatal mice lacking functional Fas death receptors are resistant to hypoxic-ischemic brain injury

Ernest M. Graham, R. Ann Sheldon, Debra L. Flock, Donna M. Ferriero, Lee J. Martin, Declan P. O'Riordan, Frances J. Northington

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


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-Tnfrsf6lpr 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-Tnfrsf6lpr mice. The selective vulnerability of the hippocampus to injury correlates with (1) lower basal expression of [Fas-associated death-domain-like IL-1β-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.

Original languageEnglish (US)
Pages (from-to)89-98
Number of pages10
JournalNeurobiology of Disease
Issue number1
StatePublished - Oct 2004


  • Apoptosis
  • Cell death phenotype
  • Hypoxia-ischemia
  • Perinatal brain injury
  • Regional brain vulnerability
  • TNF receptors
  • [Fas-associated death-domain-like IL-1β-converting enzyme]-inhibitory protein (FLIP)

ASJC Scopus subject areas

  • Neurology


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