ScienceDirect - Developmental Cell : The Nodal = Precursor Acting via Activin Receptors Induces Mesoderm by Maintaining a = Source of Its Convertases and BMP4

Volume=20 11, Issue 3 , September 2006, Pages 313-323

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doi:10.1016/j.devcel.2006.07.005 &= nbsp; 3D"How

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Article

The Nodal Precursor Acting via Activin Receptors Induces Mesoderm by=20 Maintaining a Source of Its Convertases and BMP4

Nadav Ben-Haim¹,=20 Cindy Lu²,=20 Marcela Guzman-Ayala¹,=20 Luca Pescatore¹,=20 Daniel Mesnard¹,=20 Mirko Bischofberger³,=20 Felix Naef³,=20 Elizabeth J. Robertson⁴=20 and Daniel B. Constam¹^,=20^,

¹Ecole=20 Polytechnique F=C3=A9d=C3=A9rale de Lausanne EPFL-ISREC, Chemin des = Boveresses 155,=20 CH-1066 Epalinges, Switzerland
²Harvard = Medical=20 School, Department of Neurobiology, 220 Longwood Avenue, Boston, = Massachusetts=20 02115
³National Center of Competence in = Research=20 Molecular Oncology, Chemin des Boveresses 155, CH-1066 Epalinges,=20 Switzerland
⁴Wellcome Trust Centre for = Human=20 Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7RN, United = Kingdom=20

Received 1 May 2006; revised 29 June 2006; revised = 14 July=20 2006. Published: September 1, 2006. Available online 5 = September=20 2006.

Summary

During early mouse development, the subtilisin-like proprotein = convertases=20 (SPC) Furin and PACE4 pattern the primitive ectoderm and visceral = endoderm,=20 presumably by activating the TGF=C3=9F-related Nodal precursor. Here, = mutation of the=20 SPC motif provides direct evidence that Nodal processing is essential to = specify=20 anterior visceral endoderm and mesendoderm. Surprisingly, however, the = Nodal=20 precursor binds and activates activin receptors to maintain expression = of Furin,=20 PACE4, and Bmp4 in extraembryonic ectoderm at a distance from the Nodal = source.=20 In return, Bmp4 induces Wnt3, which amplifies Nodal expression in = the=20 epiblast and mediates induction of mesoderm. We conclude that uncleaved = Nodal=20 sustains the extraembryonic source of proprotein convertases and Bmp4 to = amplify=20 Nodal signaling in two nonredundant feedback loops with dual timescales = and to=20 localize primitive streak formation at the posterior pole. Based on = mathematical=20 modeling, we discuss how these sequential loops control cell fate.=20

Author Keywords:SIGNALING; DEVBIO

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