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

Neurobiology of Disease (Oct 2004)

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

Affiliations

Ernest M. Graham: Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
R.Ann Sheldon: Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Debra L. Flock: Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Donna M. Ferriero: Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Lee J. Martin: Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Declan P. O'Riordan: Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Frances J. Northington: Department of Gyn-Ob, Division of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Journal volume & issue: Vol. 17, no. 1
pp. 89 – 98

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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