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WIREs Dev Biol
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Segmental arithmetic: summing up the Hox gene regulatory network for hindbrain development in chordates

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Organization and development of the early vertebrate hindbrain are controlled by a cascade of regulatory interactions that govern the process of segmentation and patterning along the anterior–posterior axis via Hox genes. These interactions can be assembled into a gene regulatory network that provides a framework to interpret experimental data, generate hypotheses, and identify gaps in our understanding of the progressive process of hindbrain segmentation. The network can be broadly separated into a series of interconnected programs that govern early signaling, segmental subdivision, secondary signaling, segmentation, and ultimately specification of segmental identity. Hox genes play crucial roles in multiple programs within this network. Furthermore, the network reveals properties and principles that are likely to be general to other complex developmental systems. Data from vertebrate and invertebrate chordate models are shedding light on the origin and diversification of the network. Comprehensive cis‐regulatory analyses of vertebrate Hox gene regulation have enabled powerful cross‐species gene regulatory comparisons. Such an approach in the sea lamprey has revealed that the network mediating segmental Hox expression was present in ancestral vertebrates and has been maintained across diverse vertebrate lineages. Invertebrate chordates lack hindbrain segmentation but exhibit conservation of some aspects of the network, such as a role for retinoic acid in establishing nested Hox expression domains. These comparisons lead to a model in which early vertebrates underwent an elaboration of the network between anterior–posterior patterning and Hox gene expression, leading to the gene‐regulatory programs for segmental subdivision and rhombomeric segmentation. WIREs Dev Biol 2017, 6:e286. doi: 10.1002/wdev.286 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Nervous System Development > Vertebrates: Regional Development Comparative Development and Evolution > Body Plan Evolution
The Hox gene clusters of fly, amphioxus, Ciona and mouse, and that of the putative bilaterian common ancestor. The fly Hox complement occupies two separate genomic loci, with the gap between them indicated. Chordate Hox genes are assigned to paralogue groups (PG1–15) based on their sequence features. In Ciona, the fragmented Hox loci are dispersed across two chromosomes, with one extended locus exhibiting a rearranged order of Hox paralogy and featuring multiple lengthy separations between Hox genes. In mouse, four duplicated Hox clusters are present, which have undergone numerous independent losses of multiple Hox paralogues. The colors of each gene represent their inferred evolutionary relationships to members of the ancestral Hox complement. The spatial and temporal collinearity, and RA responsiveness of vertebrate Hox gene expression across clusters are indicated. (Reprinted with permission from Ref . Copyright 2016)
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A sketch of the mouse embryonic hindbrain, in dorsal view, with rhombomeres annotated. The contributions of motor neuron pools (blue) to cranial nerves are shown in relation to the rhombomeric expression domains of Hox genes and their segmental regulators. Darker shading of Hox domains indicates higher levels of expression in particular rhombomeres. Somites (s1–3) are shown only on the left side. r, rhombomere; s, somite. (Reprinted with permission from Ref . Copyright 2016 John Wiley & Sons, Inc.)
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(a) A phylogeny of chordates depicting the inferred emergence of cis‐regulatory elements in the Hox cluster/s, based on current evidence from cis‐regulatory studies. (b) Known gene expression patterns of key components in the hindbrain GRN in invertebrate chordates and vertebrates. Homologous regions of the nervous system of amphioxus, Ciona and vertebrate embryos are depicted. Domains of RA signaling and gene expression are shown, with colors relating to the layer of the GRN in which the genes function in vertebrates (from Figure ). (c) Inferred presence/absence of GRN layers in invertebrate chordates as compared to vertebrates. The GRN hierarchy and layers correspond to those detailed in Figure . Solid lines denote presence/partial presence of the GRN layer or interaction, with dashed lines representing their absence. r, rhombomere. (Reprinted with permission from Ref . Copyright 2016)
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(a) A vertebrate phylogeny detailing the ancestry of hindbrain segmentation in relation to segmental Hox expression, sequence conservation of known segmental enhancers, and the inferred timing of whole genome duplications. (b) Time–course of segmental gene expression in the developing lamprey hindbrain. Expression of two segmental regulators, krox20 and kreisler, and three Hox genes are shown. Embryos are viewed dorsally and grouped by stage, with developmental time progressing from left to right. Three phases of Hox gene expression in the hindbrain—presegmental, segmental, and postsegmental—can be distinguished. CNE, conserved non‐coding element; r, rhombomere. (Reprinted with permission from: Ref . Copyright 2016; and Ref . Copyright 2014 Macmillan Publishers Limited, part of Springer Nature)
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The influence of signaling during hindbrain segmental patterning. (a) The shifting activity domains of retinoic acid (RA) signaling in the pre‐rhombomeric and rhombomeric hindbrain. RA from the somitic mesoderm (blue arrow) diffuses anteriorly in the neuroepithelium and is degraded by CYP26 enzymes (red), which are upregulated by FGF signaling in the isthmic organizer (IO) and display temporally dynamic expression and activity domains during development. RA activates (green arrows) expression of key genes in the developing hindbrain, including Hox PG1 factors, vHnf1 and Hoxb4. The shifting boundaries of Cyp26 expression and RA responsiveness are depicted sequentially as characterized in the pre‐rhombomeric (6–9hpf; 9–11hpf) and rhombomeric (11–18hpf) hindbrain of zebrafish embryos, but similar dynamic patterns have also been shown in mouse. (b) FGF signaling centers (green shading) in the zebrafish pre‐rhombomeric hindbrain (9–11hpf). hoxb1a activates fgf3/8 to generate an r4 signaling center. Subsequent FGF signals (green arrows) influence the expression of val/kreisler and krox20 in conjunction with vHnf1. FGF signaling from the isthmic organizer is required for correct patterning of r1. IO, isthmic organizer; pr, presumptive rhombomere; r, rhombomere.
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Regulatory principles of Hox enhancers. (a) Spatial modularity of Hoxa2 enhancer function. The mouse Hoxa2 genomic locus is depicted, with four independent enhancer elements responsible for Hoxa2 expression in the rhombomeres (r) and neural crest cells (NCC) marked with different colors (purple, green, blue, red). Each enhancer is responsible for a different spatial aspect of the overall Hoxa2 gene expression pattern, as depicted in the hindbrain schematics below. Characterized regulatory components of these enhancers, such as sites mediating inputs from Krox20 or PBX/Hox proteins, are annotated (colored text). (b) Enhancer sharing across the Hoxb cluster. A portion of the mouse Hoxb cluster containing Hoxb1‐b9 genes (gray boxes) is depicted. Colored circles represent shared neural enhancers (DE, CR3, and ENE), with arrows detailing their positive regulatory impact upon the expression of specific Hox genes within the cluster. NCC, neural crest cells; r, rhombomere; RARE, retinoic acid response element.
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Structure and features of the GRN for segmentation and A‐P Hox patterning of the hindbrain. (a) Outline of the hierarchical structure of the GRN and its constituent layers. The GRN is broadly organized into layers of circuitry mediating different aspects of the developmental process: early A‐P signaling, segmental subdivision, secondary signaling (FGF's), cell segregation and segmental patterning, culminating in rhombomeric developmental programs. Key genes and signaling molecules in each layer are highlighted, with arrows indicating the flow of regulatory information between layers. (b) Regulatory subcircuit examples from the GRN. Positive (green) and negative (red) interactions between genes are shown, with the responsible cis‐regulatory elements (blue text) annotated beside their associated genes (black text) where known.
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Repressive gene‐regulatory interactions contribute to segmental boundary positioning. Question marks indicate boundaries for which mutual repressive gene‐regulatory interactions have yet to be uncovered. r, rhombomere.
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Regulatory interactions between Hox genes and other segmentally restricted genes during hindbrain development. Aspects of the network at successive stages of the segmentation process are shown. Green and red arrows denote positive and negative gene‐regulatory interactions, respectively. Regulatory inputs from retinoic acid (blue arrows) initiate early gene expression domains in the pre‐rhombomeric hindbrain, which trigger a cascade of regulatory interactions that govern the segmental subdivision of the developing hindbrain. Segmental Hox gene expression is initiated by segmental regulators and subsequently maintained and refined by auto‐ and cross‐regulatory interactions between Hox factors. The colors of Hox gene expression are as in Figures and , with darker shading denoting higher expression levels. This interaction network is based on data from mouse, chicken, and zebrafish experiments, with genes named using mouse gene nomenclature. The pre‐rhombomeric and rhombomeric hindbrain stages depicted correspond to 7.5‐8.5dpf and 8.5‐9.5dpf mouse embryos respectively. pr, presumptive rhombomere; r, rhombomere; RA, retinoic acid. (Reprinted with permission from Ref . Copyright 2016)
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