title: A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning.
abstract: Embryogenesis depends on self-regulatory interactions between spatially separated signaling centers, but few of these are well understood. Limb development is regulated by epithelial-mesenchymal (e-m) feedback loops between sonic hedgehog (SHH) and fibroblast growth factor (FGF) signaling involving the bone morphogenetic protein (BMP) antagonist Gremlin1 (GREM1). By combining mouse molecular genetics with mathematical modeling, we showed that BMP4 first initiates and SHH then propagates e-m feedback signaling through differential transcriptional regulation of Grem1 to control digit specification. This switch occurs by linking a fast BMP4/GREM1 module to the slower SHH/GREM1/FGF e-m feedback loop. This self-regulatory signaling network results in robust regulation of distal limb development that is able to compensate for variations by interconnectivity among the three signaling pathways.
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Bénazet
authors.forename: Mirko
authors.initials: M
authors.lastname: Bischofberger
authors.forename: Eva
authors.initials: E
authors.lastname: Tiecke
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gonçalves
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
authors.forename: Aimée
authors.initials: A
authors.lastname: Zuniga
authors.forename: Felix
authors.initials: F
authors.lastname: Naef
authors.forename: Rolf
authors.initials: R
authors.lastname: Zeller
mesh_terms: D000818:Animals; D019521:Body Patterning; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005552:Forelimb / Q000196:embryology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018878:Limb Buds / Q000196:embryology / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction; D014034:Toes / Q000196:embryology; D016207:Cytokines
chemical_list: D055415:Bone Morphogenetic Protein 4; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; C525810:Bmp4 protein, mouse; C465570:Shh protein, mouse; C113178:Grem1 protein, mouse; D016207:Cytokines