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Proc Natl Acad Sci U S A September 18, 2012; 109 (38): 15354-9.

Self-regulation of the head-inducing properties of the Spemann organizer.

Inui M , Montagner M , Ben-Zvi D , Martello G , Soligo S , Manfrin A , Aragona M , Enzo E , Zacchigna L , Zanconato F , Azzolin L , Dupont S , Cordenonsi M , Piccolo S .

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.

PubMed ID: 22949641
PMC ID: PMC3458350
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: acvr1 acvr2a admp ag1 bmp2 bmp4 bmp7.1 bmp7.2 bmpr2 cer1 chrd.1 dkk1 eef1a2 egr2 frzb2 lefty mix1 myc nodal nodal1 smad1 smad4 smad4.2 szl

Article Images: [+] show captions
References [+] :
Ben-Zvi, Scaling of the BMP activation gradient in Xenopus embryos. 2008, Pubmed, Xenbase