Identification of the molecule basis on Hes1 oscillation that contributes to the heterogeneous differentiation of stem cells.

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Embryonic stem (ES) cells display heterogeneous responses upon induction of differentiation. We have shown that Hes1 expression oscillates in mouse ES cells and that this oscillating expression contributes to the heterogeneous responses. We found the following three results supported by this grant. 1. We found that Hes1 acts as an inhibitor but not as an effector of Notch signaling in ES cell differentiation and that sustained Hes1 expression promotes the preference for the mesodermal rather than the neural fate by suppression of Notch signaling. 2. We found that Hes1 depletion enhances the neural differentiation in both human ES and iPS cell lines as well as mouse ES cell lines. 3. We searched new regulators of Hes1 oscillation from affinity-purified proteins with Hes1 from mouse ES cells and found that the deubiquitinases stabilize Hes1 protein via removing ubiquitin molecules from Hes1, modulate Hes1 oscillation and regulate the neuronal differentiation of neural stem cells.