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RESEARCH PAPER
Program in Developmental Biology, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
Integration of diverse signaling pathways is essential in development and homeostasis for cells to interpret context-dependent cues. BMP and MAPK signaling converge on Smads, resulting in differential phosphorylation. To understand the physiological significance of this observation, we have generated Smad1 mutant mice carrying mutations that prevent phosphorylation of either the C-terminal motif required for BMP downstream transcriptional activation (Smad1C mutation) or of the MAPK motifs in the linker region (Smad1L mutation). Smad1C/C mutants recapitulate many Smad1-/- phenotypes, including defective allantois formation and the lack of primordial germ cells (PGC), but also show phenotypes that are both more severe (head and branchial arches) and less severe (allantois growth) than the null. Smad1L/L mutants survive embryogenesis but exhibit defects in gastric epithelial homeostasis correlated with changes in cell contacts, actin cytoskeleton remodeling, and nuclear 
-catenin accumulation. In addition, formation of PGCs is impaired in Smad1L/L mutants, but restored by allelic complementation in Smad1C/L compound mutants. These results underscore the need to tightly balance BMP and MAPK signaling pathways through Smad1.
[Keywords: Smad; TGF; MAPK; signaling; germ line; homeostasis]
Received March 11, 2004; revised version accepted April 20, 2004.
1 Present address: Centre de recherche en cancerologie de l'Université Laval, CHUQ, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec, QC, Canada G1R 2J6.
2 Corresponding author. E-MAIL psoriano{at}fhcrc.org; FAX (206) 667-6522.
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