The vertebrate segmentation clock drives segmentation by stabilizing Dusp phosphatases

Pulsatile activity of the extracellular signal-regulated kinase (ERK) regulates several cellular, developmental, and regenerative programs. Sequential segmentation of somites along the vertebrate body axis, a key developmental program, is also controlled by ERK activity oscillation. The oscillatory expression of Her/Hes family transcription factors constitute the segmentation clock, setting the period of segmentation. Although oscillation of ERK activity depends on Her/Hes proteins, the molecular mechanism of this regulation remained mysterious. Here, we show that Her/Hes proteins physically interact with and stabilize dual-specificity phosphatases (Dusp) of ERK, resulting in oscillations of Dusp4 and Dusp6 proteins. Pharmaceutical and genetic inhibition of Dusp activity disrupt ERK activity oscillation and somite segmentation. Our results reveal that post-translational interactions of Her/Hes transcription factors with Dusp phosphatases establish the fundamental vertebrate body plan. We anticipate that future studies will unearth currently unnoticed post-translational regulations of ERK pulses in other systems.