title: Self-regulation of the head-inducing properties of the Spemann organizer.
abstract: The Spemann organizer stands out from other signaling centers of the embryo because of its broad patterning effects. It defines development along the anteroposterior and dorsoventral axes of the vertebrate body, mainly by secreting antagonists of growth factors. Qualitative models proposed more than a decade ago explain the organizer's region-specific inductions (i.e., head and trunk) as the result of different combinations of antagonists. For example, head induction is mediated by extracellular inhibition of Wnt, BMP, and Nodal ligands. However, little is known about how the levels of these antagonists become harmonized with those of their targets and with the factors initially responsible for germ layers and organizer formation, including Nodal itself. Here we show that key ingredients of the head-organizer development, namely Nodal ligands, Nodal antagonists, and ADMP ligands reciprocally adjust each other's strength and range of activity by a self-regulating network of interlocked feedback and feedforward loops. A key element in this cross-talk is the limited availability of ACVR2a, for which Nodal and ADMP must compete. By trapping Nodal extracellularly, the Nodal antagonists Cerberus and Lefty are permissive for ADMP activity. The system self-regulates because ADMP/ACVR2a/Smad1 signaling in turn represses the expression of the Nodal antagonists, reestablishing the equilibrium. In sum, this work reveals an unprecedented set of interactions operating within the organizer that is critical for embryonic patterning.
authors.affiliation: Department of Biomedical Sciences,  University of Padua, 35126 Padua,  Italy.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Inui
authors.forename: Marco
authors.initials: M
authors.lastname: Montagner
authors.forename: Danny
authors.initials: D
authors.lastname: Ben-Zvi
authors.forename: Graziano
authors.initials: G
authors.lastname: Martello
authors.forename: Sandra
authors.initials: S
authors.lastname: Soligo
authors.forename: Andrea
authors.initials: A
authors.lastname: Manfrin
authors.forename: Mariaceleste
authors.initials: M
authors.lastname: Aragona
authors.forename: Elena
authors.initials: E
authors.lastname: Enzo
authors.forename: Luca
authors.initials: L
authors.lastname: Zacchigna
authors.forename: Francesca
authors.initials: F
authors.lastname: Zanconato
authors.forename: Luca
authors.initials: L
authors.lastname: Azzolin
authors.forename: Sirio
authors.initials: S
authors.lastname: Dupont
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cordenonsi
authors.forename: Stefano
authors.initials: S
authors.lastname: Piccolo
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008024:Ligands; D008954:Models, Biological; D020897:Organizers, Embryonic / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D008024:Ligands; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A