Human Molecular Genetics, 2001, Vol. 10, No. 18 1935-1944
© 2001 Oxford University Press
Frataxin deficiency enhances apoptosis in cells differentiating into neuroectoderm
1Department of Medicine, Centre Hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Québec, H2L 4M1, Canada, 2UnIGENe, Instituto de Biologia Molecular e Celular, 4150-180 Porto, Portugal
Deficiency of the mitochondrial matrix protein frataxin causes Friedreich ataxia. Frataxin function is believed to be related to mitochondrial iron metabolism and free radical production. In Friedreich ataxia, loss of dorsal root ganglia neurons occurs early in life, suggesting a developmental process. In addition, frataxin knockout mice die during embryonic life, further suggesting that frataxin is necessary for normal development. In this study we examine the role of frataxin in neuronal differentiation by using the P19 embryonic carcinoma cell line as a model system. We produced stably transfected clones with antisense or sense frataxin constructs. During retinoic acid-induced neurogenesis of frataxin-deficient cells there was a striking rise in cell death, while cell division remained unaffected. However, frataxin deficiency does not affect cell survival in cells induced to differentiate into cardiomyocytes. Frataxin deficiency enhances apoptosis of retinoic acid-stimulated cells, and the number of neuronal-like cells expressing MAP2 was dramatically reduced in these clones. In addition, we found that antisense clones induced to differentiate into neuroectoderm with retinoic acid have increased production of reactive oxygen species, and that only cells non-committed to the neuronal lineages could be rescued by the addition of the antioxidant N-acetyl-cysteine (NAC). However, NAC treatment had no effect in increasing the number of terminally differentiated neuronal-like cells in frataxin-deficient clones. Our results suggest that frataxin deficiency may render cells susceptible to apoptosis after exposure to appropriate stimuli.
+ To whom correspondence should be addressed at: Service de Neurologie, Hôpital Erasme, Route de Lennik 808, 1070 Bruxelles, Belgium. Tel: +32 2 555 33 46; Fax: +32 2 555 39 42; Email: massimo.pandolfo@ulb.ac.bePresent address:Keiichi Ohshima, Growth Factor Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
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