Semin Cell Dev Biol
January 1, 2017;
A gene regulatory program controlling early Xenopus mesendoderm formation: Network conservation and motifs.
Germ layer formation is among the earliest differentiation events in metazoan embryos. In triploblasts, three germ layers are formed, among which the endoderm
gives rise to the epithelial lining of the gut
tube and associated organs including the liver
and lungs. In frogs (Xenopus), where early germ layer formation has been studied extensively, the process of endoderm
specification involves the interplay of dozens of transcription factors. Here, we review the interactions between these factors, summarized in a transcriptional gene regulatory network (GRN). We highlight regulatory connections conserved between frog, fish, mouse, and human endodermal lineages. Especially prominent is the conserved role and regulatory targets of the Nodal
signaling pathway and the T-box transcription factors, Vegt
. Additionally, we highlight network topologies and motifs, and speculate on their possible roles in development.
Semin Cell Dev Biol
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Fig. 1. Xenopus mesendoderm gene regulatory network from fertilization through early-gastrula. The network is comprised of 35 TFs and 12 growth factors. Maternal proteins are represented as diamonds, and signaling ligands as circles. Connections are drawn from the transcriptional regulator to the cis-regulatory region of the target gene, and direct connections are indicated as solid lines and putative connections as dashed lines. Connections from secreted ligands pass through a chevron and are mediated by their respective intracellular TFs (e.g. Smad2/3, Ctnnb1/β-catenin). Approximate spatiotemporal information is provided from top to bottom (egg through early-gastrula) and from right to left (dorsal to ventral), with some exceptions (e.g. t/bra). The activation time of zygotic sox7 (boxed) is unknown. All direct connections are annotated for TF binding (blue diamond), reporter assay (pink diamond), and TF binding plus functional validation (maroon diamond). For additional connection details, including experimental evidence and references, see Table 1 and Table S2. ZGA, zygotic genome activation.
Fig. 2. Network motifs found in the Xenopus mesendoderm GRN. (A) Autoregulatory loop, for example by Nodal signaling. (B) Positive feedback loop, for example between Nodal and Wnt signaling. (C) Coherent and incoherent feedforward loops and their regulatory structure. (D) The type I feedforward loop, which appears to be the most common feedforward loop in the GRN, frequently appears in the structure such that X is a maternal factor, Y is an early zygotic gene, and Z is either an early or late zygotic gene.