Journal
JOURNAL OF CELL BIOLOGY
Volume 162, Issue 4, Pages 613-622Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200303026
Keywords
sympathetic neurons; NGF; promoter; BH3-only proteins; Forkhead transcription factors
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Funding
- Wellcome Trust Funding Source: Medline
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Developing sympathetic neurons die by apoptosis when deprived of NGF. BIM, a BH3-only member of the BCL-2 family, is induced after NGF withdrawal in these cells and contributes to NGF withdrawal-induced death. Here, we have investigated the involvement of the Forkhead box, class O (FOXO) subfamily of Forkhead transcription factors in the regulation of BIM expression by NGF. We find that overexpression of FOXO transcription factors induces BIM expression and promotes death of sympathetic neurons in a BIM-dependent manner. In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. Finally, we show that FOXO activity contributes to the NGF deprivation-induced death of sympathetic neurons.
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