Abstract
BackgroundStudies of the Xenopus organizer have laid the foundation for our understanding of the conserved signaling pathways that pattern vertebrate embryos during gastrulation. The two primary activities of the organizer, BMP and Wnt inhibition, can regulate a spectrum of genes that pattern essentially all aspects of the embryo during gastrulation. As our knowledge of organizer signaling grows, it is imperative that we begin knitting together our gene-level knowledge into genome-level signaling models. The goal of this paper was to identify complete lists of genes regulated by different aspects of organizer signaling, thereby providing a deeper understanding of the genomic mechanisms that underlie these complex and fundamental signaling events.ResultsTo this end, we ectopically overexpress Noggin and Dkk-1, inhibitors of the BMP and Wnt pathways, respectively, within ventral tissues. After isolating embryonic ventral halves at early and late gastrulation, we analyze the transcriptional response to these molecules within the generated ectopic organizers using oligonucleotide microarrays. An efficient statistical analysis scheme, combined with a new Gene Ontology biological process annotation of the Xenopus genome, allows reliable and faithful clustering of molecules based upon their roles during gastrulation. From this data, we identify new organizer-related expression patterns for 19 genes. Moreover, our data sub-divides organizer genes into separate head and trunk organizing groups, which each show distinct responses to Noggin and Dkk-1 activity during gastrulation.ConclusionOur data provides a genomic view of the cohorts of genes that respond to Noggin and Dkk-1 activity, allowing us to separate the role of each in organizer function. These patterns demonstrate a model where BMP inhibition plays a largely inductive role during early developmental stages, thereby initiating the suites of genes needed to pattern dorsal tissues. Meanwhile, Wnt inhibition acts later during gastrulation, and is essential for maintenance of organizer gene expression throughout gastrulation, a role which may depend on its ability to block the expression of a host of ventral, posterior, and lateral fate-specifying factors.
Highlights
Studies of the Xenopus organizer have laid the foundation for our understanding of the conserved signaling pathways that pattern vertebrate embryos during gastrulation
Creating ectopic organizers with separate functions using Noggin and Dkk-1 In order to describe and separate the genomic expression changes induced by the two main organizing activities, BMP inhibition and Wnt inhibition, we ectopically overexpressed one or both of these activities in ventral mesoderm, and compared these samples to endogenous dorsal and ventral mesoderm at early and late gastrula stages
To the right of the clustergram, the rank products (RP) method results at 10% false detection rate (FDR) are summarized in four columns representing the comparisons of Nog, Noggin and Dkk-1 (Nog+Dkk), Dkk, or Dor to Ven
Summary
Studies of the Xenopus organizer have laid the foundation for our understanding of the conserved signaling pathways that pattern vertebrate embryos during gastrulation. The two primary activities of the organizer, BMP and Wnt inhibition, can regulate a spectrum of genes that pattern essentially all aspects of the embryo during gastrulation. Wnt inhibitors alone cannot induce secondary structures, but when combined with Noggin can induce a complete secondary axis, including properly patterned head and trunk tissues. Inhibition of both pathways generates the complete spectrum of molecules required for total organizer function and maintenance, illustrating that regional differences in organizer activity are created by the mixes of inhibitors present and active within particular regions (reviewed in [2,3,4])
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