606 Connecting signaling dynamics with cell fates in live mice

Abstract

Many tissues are composed by multiple cell types, which are derived from and maintained by tissue resident stem cells. How stem cells coordinately differentiate into multiple cell fates is largely unclear. By using a novel ERK/MAPK signaling reporter mouse, our recent study showed that during early mouse embryogenesis, stem cells bifurcate their fates by transiently modulating ERK activation, suggesting that different cell fates can be determined by distinct types of ERK activation dynamics in stem cell differentiation. Here, we are using hair follicle as a multi-cell-type system to investigate the ERK signal-mediated cell fate coordination mechanism, as ERK pathway has been shown to regulate multiple cell fates in the hair follicle. By combining two-photon imaging approach and the ERK reporter, we are able to capture the real-time ERK signal dynamics at the single cell level throughout hair follicle regeneration in live mice, along with the cellular dynamics we have characterized before. Time-lapse analyses show that ERK signal changes its activation modes at different stages of hair follicle growth, which is coupled with the progressive cell fate specification and maintenance. Drug treatment assays uncover that distinct upstream signaling pathways contribute to different types of ERK signal activation. Further genetic manipulations are performed to understand the genesis of these ERK dynamics as well as their specific roles in coordinating cell fates and behaviors. This work bridges the gap between the dynamic activation of the key regeneration regulator and the coordinated cell fate decisions and will provide new sights into the fundamental principles of tissue regeneration. Given ERK signal is dysregulated by many oncogenes, this work will also have implications in cancer etiology and treatment.