The Nodal Precursor Acting via Activin Receptors Induces Mesoderm by Maintaining a Source of Its Convertases and BMP4

• Published in: Developmental cell 2006-09, Vol.11 (3), p.313-323
• Main Authors: Ben-Haim, Nadav, Lu, Cindy, Guzman-Ayala, Marcela, Pescatore, Luca, Mesnard, Daniel, Bischofberger, Mirko, Naef, Felix, Robertson, Elizabeth J., Constam, Daniel B.
• Format: Article
• Language: English
• Subjects: Activin Receptors - metabolism; Animals; Base Sequence; Biological and medical sciences; Body Patterning; Bone Morphogenetic Proteins - metabolism; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell receptors; Cell structures and functions; DEVBIO; Enhancer Elements, Genetic; Feedback, Physiological; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Mesoderm - physiology; Mice; Mice, Inbred C57BL; Miscellaneous; Models, Biological; Molecular and cellular biology; Molecular Sequence Data; Nodal Protein; Proprotein Convertases - metabolism; Protein Precursors - metabolism; Sequence Homology, Nucleic Acid; Signal Transduction; SIGNALING; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - physiology; Wnt Proteins - physiology; Wnt3 Protein
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2006.07.005

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.