Nodal signaling range is regulated by proprotein convertase-mediated maturation

TY - JOUR

T1 - Nodal signaling range is regulated by proprotein convertase-mediated maturation

AU - Tessadori, Federico

AU - Noël, Emily S

AU - Rens, Elisabeth G

AU - Magliozzi, Roberto

AU - Evers-van Gogh, Inkie J A

AU - Guardavaccaro, Daniele

AU - Merks, Roeland M H

AU - Bakkers, Jeroen

N1 - Copyright © 2015 Elsevier Inc. All rights reserved.

PY - 2015/3/9

Y1 - 2015/3/9

N2 - 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 reaction-diffusion system relying on the different diffusivity of an activator, Nodal, and an inhibitor, Lefty. In a genetic screen, we identified a zebrafish loss-of-function mutant for the proprotein convertase FurinA. 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 signaling activity of Spaw and no other Nodal-related factors. Combined in silico and in vivo approaches support a model in which FurinA controls the signaling range of Spaw by cleaving its proprotein into a mature, extracellular form, consequently regulating left-right patterning.

AB - 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 reaction-diffusion system relying on the different diffusivity of an activator, Nodal, and an inhibitor, Lefty. In a genetic screen, we identified a zebrafish loss-of-function mutant for the proprotein convertase FurinA. 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 signaling activity of Spaw and no other Nodal-related factors. Combined in silico and in vivo approaches support a model in which FurinA controls the signaling range of Spaw by cleaving its proprotein into a mature, extracellular form, consequently regulating left-right patterning.

U2 - 10.1016/j.devcel.2014.12.014

DO - 10.1016/j.devcel.2014.12.014

M3 - Article

C2 - 25684355

SN - 1534-5807

VL - 32

SP - 631

EP - 639

JO - Developmental Cell

JF - Developmental Cell

IS - 5

ER -