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WIREs Dev Biol
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Boundary formation in the development of the vertebrate hindbrain

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Abstract The formation of a sharp interface of adjacent subdivisions is important for establishing the precision of tissue organization, and at specific borders it serves to organize key signaling centers. We discuss studies of vertebrate hindbrain development that have given important insights into mechanisms that underlie the formation and maintenance of sharp borders. The hindbrain is subdivided into a series of segments with distinct anteroposterior identity that underlies the specification of distinct neuronal cell types. During early stages of segmentation, cell identity switching contributes to the refinement of borders and enables homogenous territories to be maintained despite intermingling of cells between segments. At later stages, there is a specific restriction to cell intermingling between segments that is mediated by Eph receptor and ephrin signaling. Eph–ephrin signaling can restrict cell intermingling and sharpen borders through multiple mechanisms, including the regulation of cell adhesion and contact inhibition of cell migration. WIREs Dev Biol 2013, 2:735–745. doi: 10.1002/wdev.106 This article is categorized under: Establishment of Spatial and Temporal Patterns > Cell Sorting and Boundary Formation

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Hindbrain segmentation. Depiction of specific aspects of neuronal organization (upper part) and segmental gene expression (lower part) to illustrate key features of hindbrain segmentation. Branchiomotor neurons arise from specific sets of rhombomeres (r), and in amniotes, such as chick, are organized in columns along the anteroposterior length of the segments; this is illustrated for the Vth, VIIth, and IXth nerves. In zebrafish, in addition to such columnar organization, specific cell types are located at a stereotypic anteroposterior location within each rhombomere: reticulospinal neurons at the center, and the fibers of radial glial cells adjacent to hindbrain boundary cells. The expression domains shown are of selected genes that have key roles in anteroposterior identity, segment formation, and cell segregation. These expression domains are conserved between species, except for the relative expression levels in different segments of some Hox genes, and which segments express EphB4 and ephrinb2; for internal consistency, the patterns shown are for zebrafish (due to genome duplication there are two orthologues of many genes, and the relevant zebrafish gene is indicated in brackets).

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Signaling of EphB receptors and ephrinBs.Selected mediators of Eph receptor and ephrin signaling are shown focusing on those that regulate cell adhesion and the actin cytoskeleton. These include proteins that are recruited upon tyrosine phosphorylation of Eph receptor or ephrinB, and mediators that bind to other motifs such as the PDZ interaction domain. Key targets of these pathways regulate the polymerization of the actin cytoskeleton, including N‐WASP, TIAM1, and Rho family kinases (Rho, Rac, Cdc42). In addition to these intracellular effectors, EphB–ephrinB interaction leads to the activation of ADAM10 that locally cleaves E‐cadherin.

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Domain structure of Eph receptors and ephrins. Conserved structural motifs of Eph receptor tyrosine kinases and of GPI‐linked ephrinA and transmembrane ephrinB proteins. The extracellular region of Eph receptors contains domains that mediate binding to ephrins and that promote clustering to form higher order complexes. Upon clustering, the kinase domain of Eph receptors is released to an active conformation and phosphorylates specific tyrosine residues in the juxtamembrane region and elsewhere. The intracellular domain of ephrinB proteins contains conserved tyrosine residues that are phosphorylated by cytoplasmic kinases. Eph receptors and ephrinB proteins each have a ‐terminal PDZ domain binding site.

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Mechanisms of border sharpening in the hindbrain. The initial fuzzy border of segments (distinct cell identity indicated with red vs green) becomes a sharp border (a). Two mechanisms can contribute to such sharpening: switching of identity of ectopic cells to match that of their predominant neighbors (b), or segregation of cells into territory that has the same identity (c). Evidence for switching comes from transplantation experiments in which it is found that at early (but not late) stages, ectopic single cells will switch identity (d), but a group of cells that remains clustered does not switch (e).

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