Abstract
BackgroundCell-cell communication is essential in tissue patterning. In early amphibian development, mesoderm is formed in the blastula-stage embryo through inductive interactions in which vegetal cells act on overlying equatorial cells. Members of the TGF-β family such as activin B, Vg1, derrière and Xenopus nodal-related proteins (Xnrs) are candidate mesoderm inducing factors, with further activity to induce endoderm of the vegetal region. TGF-β-like ligands, including BMP, are also responsible for patterning of germ layers. In addition, FGF signaling is essential for mesoderm formation whereas FGF signal inhibition has been implicated in endoderm induction. Clearly, several signaling pathways are coordinated to produce an appropriate developmental output; although intracellular crosstalk is known to integrate multiple pathways, relatively little is known about extracellular coordination.Methodology/Principal FindingsHere, we show that Xenopus Tsukushi (X-TSK), a member of the secreted small leucine rich repeat proteoglycan (SLRP) family, is expressed in ectoderm, endoderm, and the organizer during early development. We have previously reported that X-TSK binds to and inhibits BMP signaling in cooperation with chordin. We now demonstrate two novel interactions: X-TSK binds to and inhibits signaling by FGF8b, in addition to binding to and enhancement of Xnr2 signaling. This signal integration by X-TSK at the extracellular level has an important role in germ layer formation and patterning. Vegetally localized X-TSK potentiates endoderm formation through coordination of BMP, FGF and Xnr2 signaling. In contrast, X-TSK inhibition of FGF-MAPK signaling blocks ventrolateral mesoderm formation, while BMP inhibition enhances organizer formation. These actions of X-TSK are reliant upon its expression in endoderm and dorsal mesoderm, with relative exclusion from ventrolateral mesoderm, in a pattern shaped by FGF signals.Conclusions/SignificanceBased on our observations, we propose a novel mechanism by which X-TSK refines the field of positional information by integration of multiple pathways in the extracellular space.
Highlights
During blastula stages of amphibian development, the embryo is organized into three distinct germ layers: ectoderm, mesoderm and endoderm, precursors of skin, connective tissue and gut respectively
Chd does not inhibit MAPK phosphorylation in animal explants, which is supported by the observation that Xbra expression, requiring intact FGF-MAPK signaling [22], is not affected upon Chd overexpression. These results demonstrate that the action of Xenopus Tsukushi (X-TSK) upon MAPK and Smad2 is not mediated through Bone Morphogenetic Proteins (BMPs) antagonism, and suggests potential mechanisms underlying X-TSK function in germ layer formation and patterning, which we have examined in further detail
We describe three major functions of X-TSK: activation of endoderm formation, inhibition of ventrolateral mesoderm formation, and expansion of dorsal mesoderm
Summary
During blastula stages of amphibian development, the embryo is organized into three distinct germ layers: ectoderm, mesoderm and endoderm, precursors of skin, connective tissue and gut respectively. Studies on mesoderm formation have identified several mesoderm-inducing factors; Activin B [4], Vg1 [5], Derriere [6] and Xenopus nodal-related proteins (Xnrs), [7,8] members of the activin-like branch of the Transforming Growth Factor-b (TGF-b) family of signaling molecules These proteins act as morphogens and demonstrate activity to induce dorsal mesoderm formation at higher concentrations [9,10]. We demonstrate two novel interactions: X-TSK binds to and inhibits signaling by FGF8b, in addition to binding to and enhancement of Xnr signaling This signal integration by X-TSK at the extracellular level has an important role in germ layer formation and patterning. We propose a novel mechanism by which X-TSK refines the field of positional information by integration of multiple pathways in the extracellular space
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