Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain

Hoekman, Marco F.M.; Jacobs, Frank M. J.; Smidt, Marten P.; Burbach, J. Peter H.

doi:10.1016/j.modgep.2005.07.003

Cited by 168 publications

(148 citation statements)

References 13 publications

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“…FOXO3a is highly expressed in human brain, specifically in those areas that are highly vulnerable to neurodegeneration in Alzheimer's disease (Hoekman et al, 2006). We identified this isoform as a direct Cdk5 substrate by our chemical genetic screen using mouse brain lysates.…”

Section: Discussionmentioning

confidence: 99%

“…Using an innovative chemical genetic screen, we identified transcription factor Foxo3 (murine isoform) as a new substrate of Cdk5 kinase in mouse brain lysates. Among the four mammalian forkhead transcription factors of the O class (FOXOs), FOXO1 and FOXO3a are highly expressed in the human brain, specifically in areas vulnerable to Alzheimer's disease (Hoekman et al, 2006). FOXOs regulate diverse cellular processes including oxidative stress resistance and apoptosis (Fukunaga et al, 2005;Klotz et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

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Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2). However, following prolonged exposure, Foxo3 upregulated Bim (also known as BCL2L11) and FasL (also known as FASLG) causing cell death. Active Foxo3 also increased Aβ(1-42) levels in a phosphorylationdependent manner. These events were completely inhibited either by expressing phosphorylation-resistant Foxo3 or by depleting Cdk5 or Foxo3, highlighting a key role for Cdk5 in regulating Foxo3. These results were confirmed in an Alzheimer's disease mouse model, which exhibited increased levels and nuclear localization of Foxo3 in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, indicating this phenomenon is an early event in Alzheimer's disease pathogenesis. Collectively, these results show that Cdk5-mediated phospho-regulation of Foxo3 can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

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“…In mammals, multiple family members exist for many components of the pathway including three isoforms for each of the Class IA PI3K subunits, three AKT isoforms, three FOXO family members and two S6K isoforms. AFX, respectively), all three of which are expressed in brain (Hoekman et al, 2006;Lein et al, 2007). AKT phosphorylation of the FOXO (forkhead) family of transcription factors negatively regulates their activity by inducing their release from DNA and translocation to the cytoplasm where they are retained by binding to 14-3-3 proteins (Brunet et al, 1999).…”

Section: Downstream Of Aktmentioning

confidence: 99%

PTEN signaling in brain: neuropathology and tumorigenesis

2008

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“…The most recently identified FoxO family member, FoxO6, is unique in that its mRNA is expressed predominantly in the CNS in mammals (Jacobs et al 2003;Hoekman et al 2006), whereas FoxO1, FoxO3, and FoxO4 are expressed relatively ubiquitously (Furuyama et al 2000;Biggs et al 2001;Hoekman et al 2006). FoxO6 mRNA is particularly highly expressed in the hippocampus (Jacobs et al 2003;Hoekman et al 2006), a region important for learning and memory.…”

mentioning

confidence: 99%

“…FoxO6 mRNA is particularly highly expressed in the hippocampus (Jacobs et al 2003;Hoekman et al 2006), a region important for learning and memory. Like other FoxO family members, FoxO6 is negatively regulated by the insulin/IGF signaling pathway in cells.…”

mentioning

confidence: 99%

FoxO6 regulates memory consolidation and synaptic function

et al. 2012

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The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.

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Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain

Cited by 168 publications

References 13 publications

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

PTEN signaling in brain: neuropathology and tumorigenesis

FoxO6 regulates memory consolidation and synaptic function

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