Morphogen gradient interpretation by a regulated trafficking step during ligand–receptor transduction

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Abstract
Morphogen gradients are important in early development, but how cells recognize their position in such a gradient is not well understood. Cells need to correctly interpret a morphogen concentration when the morphogen is no longer present in the extracellular medium. This memory of morphogen exposure is necessary for correct cell fate decisions in the changing morphogen gradient concentration in an embryo. Our results demonstrate that a previously unrecognized step in gradient interpretation is a temporal stop that arrests the progression of a ligand–receptor complex between internalization and lysosomal destruction. Signaling continues during this arrested progression, which constitutes the basis of memory of morphogen concentration. We show that prolonged signaling requires Dynamin-dependent internalization of the complex. Rab5QL- and Rab7QL-mediated increases in the speed of the endo-lysosomal progression do not affect memory. In contrast, memory is abolished by increasing the targeting of receptors to the lysosome through expression of the Smad7/Smurf2 ubiquitin ligase. We conclude that the basis for memory is the long-lasting residence of a signaling complex in the endo-lysosomal pathway. The regulated duration of this step helps to determine the choice of gene expression resulting from gradient interpretation.