title: The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4.
abstract: During early mouse development, the subtilisin-like proprotein convertases (SPC) Furin and PACE4 pattern the primitive ectoderm and visceral endoderm, presumably by activating the TGFss-related Nodal precursor. Here, mutation of the SPC motif provides direct evidence that Nodal processing is essential to specify anterior visceral endoderm and mesendoderm. Surprisingly, however, the Nodal precursor binds and activates activin receptors to maintain expression of Furin, PACE4, and Bmp4 in extraembryonic ectoderm at a distance from the Nodal source. In return, Bmp4 induces Wnt3, which amplifies Nodal expression in the epiblast and mediates induction of mesoderm. We conclude that uncleaved Nodal sustains the extraembryonic source of proprotein convertases and Bmp4 to amplify Nodal signaling in two nonredundant feedback loops with dual timescales and to localize primitive streak formation at the posterior pole. Based on mathematical modeling, we discuss how these sequential loops control cell fate.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne EPFL-ISREC, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
authors.forename: Nadav
authors.initials: N
authors.lastname: Ben-Haim
authors.forename: Cindy
authors.initials: C
authors.lastname: Lu
authors.forename: Marcela
authors.initials: M
authors.lastname: Guzman-Ayala
authors.forename: Luca
authors.initials: L
authors.lastname: Pescatore
authors.forename: Daniel
authors.initials: D
authors.lastname: Mesnard
authors.forename: Mirko
authors.initials: M
authors.lastname: Bischofberger
authors.forename: Felix
authors.initials: F
authors.lastname: Naef
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Constam
mesh_terms: D029404:Activin Receptors / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D055457:Nodal Protein; D043484:Proprotein Convertases / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology; D060508:Wnt3 Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse; D029404:Activin Receptors; D043484:Proprotein Convertases