Research is centered around the molecular mechanisms involved in:
1. cortical development
2. neural stem cell maintenance
Our interest in how transcription factors 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, but little is known about the time and place dependent role of FoxOs within this context. We have shown that FoxO6 is crucial for the correct migration of neurons during embryonic cortical development via direct transcriptional regulation of semaphorin-linked PlxnA4 (Paap et al, PNAS 2016). Recent data from our lab indicate that FoxO6 is not only involved in correct neuronal migration, but also plays a role in neuronal differentiation and maturation, pointing to a multifunctional role during brain development. At the moment, we are working on deciphering the involved mechanisms.
The second line of research involves the transcription factor driven maintenance of neural stem cells. In contrast to embryonic neural stem cells (neuroepithelial cells and radial glia) stem cells residing in the adult brain exist in a quiescent state, only to start proliferating in a strictly controlled manner. We are specifically interested in the molecular context of adult neural stem cells deciding to exit quiescence. Next to metabolism and stress, circadian rhythmicity is an important aspect in the transition between the quiescent and proliferating stem cell state. 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 in liver 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). On the basis of recent data from our lab, we hypothesize that a similar mechanism is involved in the regulation of NSC maintenance in the adult hippocampus and the embryonic cortex. At the moment studies are underway to test this hypothesis (Draijer et al. 2018, Prog Neurobiol).
The circadian clock in adult neural stem cell maintenance. Draijer S, Chaves I and Hoekman MFM Prog. Neurobiol. 2018
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