Dev112649 477..485

Proper tissuedevelopment requires that stem/progenitorcells precisely coordinate cell division and differentiation in space and time. NotchHes1 intercellular signaling, which affects both differentiation and cell cycle progression and directs cell fate decisions at various developmental stages in many cell types, is central to this process. This study explored whether the pattern of connections among the cell cycle regulatory module, the Notch effector Hes1 and the proneural factor Ngn2 could explain salient aspects of cell fate determination in neural progenitors. A mathematical model that includes mutual interactions between Hes1, Ngn2 and G1-phase regulators was constructed and simulated at the singleand two-cell levels. By differentially regulating G1-phase progression, Hes1 and Ngn2 are shown to induce two contrasting cell cycle arrest states in early and late G1, respectively. Indeed, steady Hes1 overexpression promotes reversible quiescence by downregulating activators of G0/G1 exit and Ngn2. Ngn2 also downregulates activators of G0/G1 exit, but cooperates with Cip/Kip proteins to prevent G1/S transit, whereby it promotes G1-phase lengthening and, ultimately, contributes to reinforcing an irreversible late G1 arrest coincident with terminal differentiation. In this scheme, Hes1 oscillation in single cells is able to maintain a labile proliferation state in dynamic balance with two competing cell fate outputs associated with Hes1-mediated and Ngn2mediated cell cycle arrest states. InDelta/Notch-connected cells, Hes1 oscillations and a lateral inhibition mechanism combine to establish heterogeneous Hes1, Ngn2 and cell cycle dynamics between proliferating neural progenitors, thereby increasing the chances of asymmetric cell fate decisions and improving the reliability of commitment to differentiation.