Overall, our exploration of HES1 and HES5 in the same cell suggests that a co-expressing hybrid state is enabled by oscillatory dynamics and synchronisation at single cell level.

Using in vivo data, we show that the fraction of neural progenitor cells that co-express HES1 and HES5 becomes reduced between E9.5 and E10.5. This is supported by analysis of existing transcriptomics data showing that progenitors are exiting the hybrid state during development.

In the coupled model, the resolution of the cross-repressive motif into a single dominant HES occurs through a change in cross-repression threshold and/or level; this suggests that a similar process could occur during development to give rise to separate HES1 and HES5 expression domains.

Using a computational model of HES protein repressing mRNA, we find that differences in protein stability give them distinct free-running oscillatory periods, but co-expression results in phase-locking, with slower HES5 entraining faster HES1.

Using in-vitro neural progenitor cultures and timelapse imaging, we show that most cells are in a hybrid HES1/HES5 state characterised by co-oscillation at a common 3-4h period. At the same time, a minority of progenitors show resolution of the hybrid state into one dominant HES.