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Etiology and Pathogenesis
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Stem Cells
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Developmental Cell, Volume 11, Issue 3,
September 2006, Pages 313-323, doi:10.1016/j.devcel.2006.07.005,
Available online 5 September 2006
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Abstract |
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The Nodal Precursor Acting via Activin
Receptors Induces Mesoderm by Maintaining a Source of Its Convertases
and BMP4
Nadav Ben-Haim 1,
Cindy Lu2, Marcela Guzman-Ayala1,
Luca Pescatore1, Daniel Mesnard1,
Mirko Bischofberger3, Felix Naef3,
Elizabeth J. Robertson4 and Daniel B.
Constam1,*
1Ecole Polytechnique Fédérale de Lausanne EPFL-ISREC,
Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. 2Harvard
Medical School, Department of Neurobiology, 220 Longwood Avenue,
Boston, Massachusetts 02115. 3National Center of Competence
in Research Molecular Oncology, Chemin des Boveresses 155, CH-1066
Epalinges, Switzerland. 4Wellcome Trust Centre for Human
Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7RN,
United Kingdom -- *Corresponding author. Email: daniel.constam@isrec.ch.
-- Received 1 May 2006; revised 29 June 2006; revised 14
July 2006. Published: September 1, 2006. Available online
5 September 2006.
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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.
Author Keywords: SIGNALING;
DEVBIO
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Copyright © 2006 Elsevier B.V. All
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