title: c-fos controls the "private pathway" of light-induced apoptosis of retinal photoreceptors.
abstract: White light (5 klux for 2 hr) induces apoptosis of rod photoreceptors in wild-type mice (c-fos(+/+)) within 24 hr, whereas rods of c-fos knock-out mice (c-fos(-/-)) are protected (). The range of this protection was tested by analyzing retinas of c-fos(+/+) and c-fos(-/-) mice up to 10 d after exposure to threefold increased light intensities (15 klux for 2 hr). In c-fos(-/-) mice, rods were unaffected, whereas they were destroyed in c-fos(+/+) mice. After light exposure, mitochondrial damage in rods was observed exclusively in c-fos(+/+) mice. Electroretinograms recorded 48 hr after exposure revealed a decrease of all components in c-fos(+/+) mice but indicated no light-induced loss of function in c-fos(-/-) mice. Thus, in c-fos(-/-) mice, light-induced apoptosis is blocked or its threshold is elevated more than threefold. Increased activity of the transcription factor activator protein-1 (AP-1) in retinas of light-exposed c-fos(+/+) mice indicated an acute contribution of AP-1 to apoptosis induction. AP-1 activity increased already during exposure and peaked approximately 6 hr thereafter, coinciding with the appearance of major morphological signs of apoptosis. Activated AP-1 mainly consisted of c-Fos/Jun heterodimers. In c-fos(-/-) mice, AP-1 activity remained unchanged, indicating that no other Jun- or Fos-family member could substitute for c-Fos. Like damaging light, N-methyl-N-nitrosourea (MNU) induced AP-1 containing c-Fos in c-fos(+/+) mice and did not induce AP-1 in c-fos(-/-) mice. In contrast to light, however, MNU induced apoptosis in rods of c-fos(-/-) mice. Thus, c-Fos is essential for a specific premitochondrial "private apoptotic pathway" induced by light but not for the execution of apoptosis induced by other stimuli.
authors.affiliation: Department of Ophthalmology, University Hospital Zürich, CH-8091 Zürich, Switzerland. awenzel@opht.unizh.ch
authors.forename: A
authors.initials: A
authors.lastname: Wenzel
authors.forename: C
authors.initials: C
authors.lastname: Grimm
authors.forename: A
authors.initials: A
authors.lastname: Marti
authors.forename: N
authors.initials: N
authors.lastname: Kueng-Hitz
authors.forename: F
authors.initials: F
authors.lastname: Hafezi
authors.forename: G
authors.initials: G
authors.lastname: Niemeyer
authors.forename: C E
authors.initials: CE
authors.lastname: Remé
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003623:Dark Adaptation / Q000502:physiology; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D008027:Light / Q000009:adverse effects; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology* / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D008770:Methylnitrosourea