Interaction of Wnt and SHH gradients synchronizes cell cycle 1 exit and differentiation

Abstract

Classic models of the French flag problem depict sharp cell-type boundaries emerging from threshold responses to morphogen gradients. Yet, how such boundaries arise during dynamic cell-state transitions remains unclear. We use hair follicle dermal condensates to study a sharp cell-type transition in which proliferative progenitors synchronously undergo cell-cycle exit and molecular differentiation. Using genetic and genomic approaches, we show that Wnt and Hedgehog signaling interact to coordinate the timing of these processes. When their activities are temporally aligned, intermediate transitional states are compressed through cell-cycle exit, producing a sharp cell-type boundary; when misaligned, transitional states expand, yielding fuzzy borders. Mechanistically, elevated Wnt activity promotes cell-cycle exit by regulating chromatin binding of the Hedgehog mediator GLI3. Hedgehog signaling induces differentiation genes in a Wnt-dependent manner and simultaneously elevates Wnt activity, aligning arrest and differentiation in time. These findings reveal a mechanism wherein morphogen interactions coordinate transitions to generate precise cell-type boundaries.