title: Nodal signaling range is regulated by proprotein convertase-mediated maturation.
abstract: 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.
authors: Cardiac Development and Genetics, Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Federico
authors: F
authors: Tessadori
authors: Cardiac Development and Genetics, Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Emily S
authors: ES
authors: Noël
authors: Life Sciences Group, Centrum Wiskunde and Informatica, 1098 XG Amsterdam, the Netherlands; Mathematical Institute, Leiden University, 2333 CA Leiden, the Netherlands.
authors: Elisabeth G
authors: EG
authors: Rens
authors: Cardiac Development and Genetics, Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Roberto
authors: R
authors: Magliozzi
authors: Cardiac Development and Genetics, Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Inkie J A
authors: IJ
authors: Evers-van Gogh
authors: Cardiac Development and Genetics, Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors: Daniele
authors: D
authors: Guardavaccaro
authors: Life Sciences Group, Centrum Wiskunde and Informatica, 1098 XG Amsterdam, the Netherlands; Mathematical Institute, Leiden University, 2333 CA Leiden, the Netherlands.
authors: Roeland M H
authors: RM
authors: Merks
authors: Cardiac Development and Genetics, Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands. Electronic address: j.bakkers@hubrecht.eu.
authors: Jeroen
authors: J
authors: Bakkers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019521:Body Patterning / Q000502:physiology; D005455:Fluorescent Antibody Technique; D017403:In Situ Hybridization; D055458:Left-Right Determination Factors / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D055457:Nodal Protein / Q000378:metabolism*; D043484:Proprotein Convertases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015027:Zebrafish / Q000254:growth & development* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D055458:Left-Right Determination Factors; D055457:Nodal Protein; D012333:RNA, Messenger; D029961:Zebrafish Proteins; C551315:FurinA protein, zebrafish; D043484:Proprotein Convertases