title: Smad1 transcription factor integrates BMP2 and Wnt3a signals in migrating cardiac progenitor cells.
abstract: In vertebrate embryos, cardiac progenitor cells (CPCs) undergo long-range migration after emerging from the primitive streak during gastrulation. Together with other mesoderm progenitors, they migrate laterally and then toward the ventral midline, where they form the heart. Signals controlling the migration of different progenitor cell populations during gastrulation are poorly understood. Several pathways are involved in the epithelial-to-mesenchymal transition and ingression of mesoderm cells through the primitive streak, including fibroblast growth factors and wingless-type family members (Wnt). Here we focus on early CPC migration and use live video microscopy in chicken embryos to demonstrate a role for bone morphogenetic protein (BMP)/SMA and MAD related (Smad) signaling. We identify an interaction of BMP and Wnt/glycogen synthase kinase 3 beta (GSK3β) pathways via the differential phosphorylation of Smad1. Increased BMP2 activity altered migration trajectories of prospective cardiac cells and resulted in their lateral displacement and ectopic differentiation, as they failed to reach the ventral midline. Constitutively active BMP receptors or constitutively active Smad1 mimicked this phenotype, suggesting a cell autonomous response. Expression of GSK3β, which promotes the turnover of active Smad1, rescued the BMP-induced migration phenotype. Conversely, expression of GSK3β-resistant Smad1 resulted in aberrant CPC migration trajectories. De-repression of GSK3β by dominant negative Wnt3a restored normal migration patterns in the presence of high BMP activity. The data indicate the convergence of BMP and Wnt pathways on Smad1 during the early migration of prospective cardiac cells. Overall, we reveal molecular mechanisms that contribute to the emerging paradigm of signaling pathway integration in embryo development.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Junfang
authors.initials: J
authors.lastname: Song
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: McColl
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Esther
authors.initials: E
authors.lastname: Camp
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Niki
authors.initials: N
authors.lastname: Kennerley
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Gi Fay
authors.initials: GF
authors.lastname: Mok
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Dominique
authors.initials: D
authors.lastname: McCormick
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Grocott
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Grant N
authors.initials: GN
authors.lastname: Wheeler
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom a.munsterberg@uea.ac.uk.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Münsterberg
mesh_terms: D000818:Animals; D019521:Body Patterning; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000196:embryology; D008648:Mesoderm / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D054240:Primitive Streak / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*; D060509:Wnt3A Protein / Q000378:metabolism*
chemical_list: D055396:Bone Morphogenetic Protein 2; D051898:Smad1 Protein; D060509:Wnt3A Protein; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: cell tracking; live imaging