Matrix metalloproteinases (MMPs) are a large family of proteins in vertebrates, consisting of ove... more Matrix metalloproteinases (MMPs) are a large family of proteins in vertebrates, consisting of over 24 genes in humans, only a few of which have been identified in Xenopus. Three genes coding for MMPs in Xenopus have been identified and their expression studied during development. The membrane-bound XMMP-14 and -15 (XMT1-MMP and XMT2-MMP) both showed restricted expression patterns, the former principally localising to cranial neural crest tissues and the latter to the epidermis of the embryo. XMMP-7 codes for an MMP that lacks the hemopexin-like domain. It is expressed exclusively in macrophages or other myeloid cell types from early in development. Developmental Dynamics 231:214 -220, 2004.
Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is ... more Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is an important goal, as such
Proceedings of the National Academy of Sciences of the United States of America, 2014
In vertebrate embryos, cardiac progenitor cells (CPCs) undergo long-range migration after emergin... more 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.
Matrix metalloproteinases (MMPs) are a large family of proteins in vertebrates, consisting of ove... more Matrix metalloproteinases (MMPs) are a large family of proteins in vertebrates, consisting of over 24 genes in humans, only a few of which have been identified in Xenopus. Three genes coding for MMPs in Xenopus have been identified and their expression studied during development. The membrane-bound XMMP-14 and -15 (XMT1-MMP and XMT2-MMP) both showed restricted expression patterns, the former principally localising to cranial neural crest tissues and the latter to the epidermis of the embryo. XMMP-7 codes for an MMP that lacks the hemopexin-like domain. It is expressed exclusively in macrophages or other myeloid cell types from early in development. Developmental Dynamics 231:214 -220, 2004.
Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is ... more Elucidating the gene regulatory networks that govern pharyngeal arch artery (PAA) development is an important goal, as such
Proceedings of the National Academy of Sciences of the United States of America, 2014
In vertebrate embryos, cardiac progenitor cells (CPCs) undergo long-range migration after emergin... more 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.
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Papers by Tim Grocott