An acid switch decouples BMP gradient formation from morphogenetic signaling

Morphogen gradients shape morphological patterns, yet morphogen long-range dispersal and signaling pose a paradox: dispersal requires weak receptor binding, but strong binding is needed for signaling from a diluted morphogen. We show that the fly BMP2/4 homolog Dpp resolves this via a pH-dependent receptor switch. In the neutral extracellular space, Dpp binds weakly to the glypican Dally instead of the signaling receptor Tkv. Dally internalizes Dpp and delivers it via endosomal fusion to an acidic compartment, where Dpp shifts to bind Tkv, activating signaling. A key histidine in Dpp mediates this transition. Later, pH neutralization in the recycling pathway releases Dpp, replenishing the extracellular gradient. This mechanism, conserved in mammalian BMP2, enables efficient morphogen dispersal, robust signaling, and gradient scaling with tissue size. By dynamically shifting receptor interactions based on pH, cells reconcile long-range morphogen movement and strong intracellular signaling, ensuring precise long-rage pattern formation and scaling during development.