Research in our lab is centered around the molecular mechanisms underlying cortical development and circadian rhythms. Specifically, we are interested in how transcriptional programs are involved in the formation of cortical structures and the regulation of ciradian rhythmicity.
Our interest in how transcriptional programs shape the developing and adult brain started when screening for transcription factors expressed in the adult mouse hippocampus. As a direct consequence, a novel member of the mammalian FoxO family, FoxO6, was discovered (Jacobs et al. 2003, J Biol Chem). Apart from analyzing the expression profile in the embryonic and adult brain, we performed several functional studies, one of which showed that FoxO6, in contrast to the other FoxOs, is not able to translocate from the nucleus to the cytoplasm. Normally, FoxOs are responsive to insulin and insulin-like growth factors, rendering them inactive via PKB-dependent translocation to the cytoplasm. Although FoxO6 lost its ability to modulate its transcriptional activity via translocation, it is still capable of regulating downstream targets.
Currently, we are working on how FoxO transcrption factors are involved in cortex development. All four mammalian FoxO family members are expressed in the embryonic cortex in an overlapping and complementary manner. Next to using transgenic mouse models we have the in utero electroporation technique running in the lab, enabling us to alter expression of the studied genes in the vivo cortex. Recently, we published a study showing how FoxO6 is involved in neuronal migration by regulation of Plxna4, a known molecular component of the Semaphorin signaling pathway. (Paap et al. 2016, PNAS).
The second line of research involves the regulation of circadian rhythms via insulin-dependent and FoxO3-mediated signaling. In collaboration with Dr. I. Chaves and Prof. G.van der Horst (Molecular Chronobiology, Erasmus MC) we have shown that FoxO3 is crucial for circadian rhythms amplitude through direct transcriptional regulation of Clock, one of the core-clock components. Moreover, we were able to modulate circadian rhythm amplitude by the use of insulin (Chaves et al. 2014, Current Biology). At the moment studies are underway to unravel the role of circadian rhythms in both the developing and adult brain.
FoxO6 affects PlxnA4-mediated neuronal migration during mouse cortical development.
Paap RH, Oosterbroek S, Wagemans CM, von Oerthel L, Schellevis RD, Vastenhouw-van der Linden AJ, Groot Koerkamp MJ, Hoekman MFM and Smidt MP. PNAS 2016 Shared Last author and co-corresponding.
Insulin-FoxO3 signaling modulates circadian rhythms via regulation of clock transcription.
Chaves I, van der Horst GT, Schellevis RD, Nijman RM, Koerkamp MG, Holstege MC, Smidt MP and Hoekman MFM. Current Biology 2014 Last author and corresponding.
Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain.
Hoekman MFM, Jacobs FM, Smidt MP and Burbach JP. Gene Expr Patterns 2006
The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.
van der Heide LP, Hoekman MFM and Smidt MP. Biochem J 2004
FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics.
Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MFM and Smidt MP. J Biol Chem 2003