Name MFM Hoekman (Marco)
Department of Neuroscience and Pharmacology
Section Neurodevelopment
Function Assistant professor
E-mail:
m.f.m.hoekman@umcutrecht.nl Tel: +31 88 7568638
Title research line FoxO transcription factors in neuronal survival and maintenance
Summary research Development and plasticity of neuronal systems relies on explicit programs of gene expression. These expression programs are internally driven by transcription factors, and are under the tight control of external signals provided by growth factors, neurotransmitters and cell surface proteins. One particular interesting class of transcription factors which has been known to couple external stimuli to gene regulation is the the forkhead (Fox) or winged helix family of transcription factors, including the foxO members FoxO1, FoxO3 and FoxO4. FoxO factors form a transcriptional endpoint of the PI3-kinase/PKB signal transduction pathway, activated by several growth factors, like insulin, IGF-1, NGF and BDNF (Accili et al., Burgering et al., Gan et al., Essers et al.). Transfected in cell lines, FoxO members display a unique shuttling behavior between the nucleus and the cytosol under the control of PI3-kinase/PKB-mediated phosphorylation. Activation of this pathway leads to phosphorylation of FoxO proteins, and to relocation from the nucleus to the cytoplasm, thereby abolishing transcriptional activity. In vitro and ex vivo evidence indicates FoxO transcription factors to be directly involved in neuronal cell survival, acting as pro-apoptotic proteins and as downstream targets of the insulin-induced PI3-kinase/PKB signal transduction pathway.
A fourth murine FoxO member, FoxO6 was identified in our lab (Jacobs et al., van der Heide et al., Hoekman et al). During development FoxO6 is expressed mainly in the forebrain. Moreover, structure-function analysis in cell lines stimulated by growth factors, revealed that FoxO6 differs markedly in the dynamics of shuttling between nucleus and cytosol from FoxO1 and FoxO3. Interestingly, the expression of FoxO factors in the brain appears strictly regulated in a spatiotemporal fashion during development, precipitating in a specific expression profile in the adult brain. The hippocampus specifically, displays complementary and partly overlapping expression domains of FoxO1,-O3, and -O6 in the separate CA fields and the dentate gyrus area, suggesting a FoxO-regionalisation code within this neuronal structure. Notably, hippocampal expression of FoxO genes is induced only late in brain development at stages when pyramidal cells in the CA subfields and granule cells in the dentate gyrus develop and functional networks are formed. Moreover, expression is prominent in the mature hippocampus, possibly pointing to the regulatory potential of FoxO genes in adult hippocampal physiology.
Taken together, FoxO transcription factors, specifically FoxO6, are in a key position to participate in signal transduction cascades which determine neuronal fate and plasticity. Therefore, the overall aim of this program is to determine the involvement of the forkhead transcription factor FoxO6 in neuronal development, thereby linking FoxO mediated survival and maintanance to neuronal differentiation.
Publications: Wijchers PJ, Hoekman MFM, Burbach JP, Smidt MP (2006)
Identification of forkhead transcription factors in cortical and dopaminergic areas of the adult murine brain.
Hoekman MFM, Jacobs FM, Smidt MP, Burbach JP (2006)
Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain.
van der Heide LP, Jacobs FM, Burbach JP, Hoekman MFM, Smidt MP (2005)
FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling.
van der Heide LP, Hoekman MFM, Smidt MP (2005)
The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.
Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MFM, Smidt MP (2004)
FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics.