Nodal Signaling Range Is Regulated by Proprotein Convertase-Mediated Maturation

Tissue patterning is established by extracellular growth factors or morphogens. Although different theoretical models explaining specific patterns have been proposed, our understanding of tissue pattern establishment in vivo remains limited. In many animal species, left-right patterning is governed by a reac- tion-diffusion system relying on the different diffu- sivity of an activator, Nodal, and an inhibitor, Lefty. In a genetic screen, we identified a zebrafish loss- of-function mutant for the proprotein convertase Fur- inA. Embryological and biochemical experiments demonstrate that cleavage of the Nodal-related Spaw proprotein into a mature form by FurinA is required for Spaw gradient formation and activation of Nodal signaling. We demonstrate that FurinA is required cell-autonomously for the long-range sig- naling activity of Spaw and no other Nodal-related factors. Combined in silico and in vivo approaches support a model in which FurinA controls the sig- naling range of Spaw by cleaving its proprotein into a mature, extracellular form, consequently regulating left-right patterning.