Bruce AEE and Winklbauer R (2020), Brachyury in the gastrula of basal vertebrates.

XB-ART-57088

Mech Dev 2020 Sep 01;163:103625. doi: 10.1016/j.mod.2020.103625.

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Brachyury in the gastrula of basal vertebrates.

Bruce AEE , Winklbauer R .

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The Brachyury gene encodes a transcription factor that is conserved across all animals. In non-chordate metazoans, brachyury is primarily expressed in ectoderm regions that are added to the endodermal gut during development, and often form a ring around the site of endoderm internalization in the gastrula, the blastopore. In chordates, this brachyury ring is conserved, but the gene has taken on a new role in the formation of the mesoderm. In this phylum, a novel type of mesoderm that develops into notochord and somites has been added to the ancestral lateral plate mesoderm. Brachyury contributes to a shift in cell fate from neural ectoderm to posterior notochord and somites during a major lineage segregation event that in Xenopus and in the zebrafish takes place in the early gastrula. In the absence of this brachyury function, impaired formation of posterior mesoderm indirectly affects the gastrulation movements of peak involution and convergent extension. These movements are confined to specific regions and stages, leaving open the question why brachyury expression in an extensive, coherent ring, before, during and after gastrulation, is conserved in the two species whose gastrulation modes differ considerably, and also in many other metazoan gastrulae of diverse structure.

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Species referenced: Xenopus laevis
Genes referenced: tbxt
GO keywords: cell fate determination [+]

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	Fig. 1. Gastrula-stage brachyury expression in metazoans. (A) Zebrafish brachyury (tbxa) expression as seen by in situ hybridization, from early (left) to late gastrula stages (right). Dorsal (left, mid-left, mid-right) and vegetal view (right), respectively. MZ, marginal zone; n, notochord anlage; nt, nascent tailbud. (B) Gastrula-stage brachyury pattern schemata in select metazoan groups. Red, brachyury expression at blastopore. Dorsal view with animal pole to the top, except Protostomia, which are viewed from vegetal (slit-like blastopore indicated). (C) Phylogenetic relationships of vertebrate groups mentioned in text. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
	Fig. 2. Brachyury expression in select deuterostomes at blastula-gastrula transition. Top row: fate maps; middle row: brachyury expressing regions at same stages. Brachyury expression (red) is in the ectoderm in sea urchins, in mesoderm and endoderm in Branchiostoma, and in mesoderm in Xenopus. Bottom row: sagittal section through sea urchin and Branchiostoma embryo after gastrulation (for Xenopus, see Fig. 4). For orientation, endoderm and non-neural, neural ectoderm are indicated in addition to brachyury expression (red) in the cross-sections. arc, archenteron. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
	Fig. 3. Mesoderm development in chordates. (A-A″) Notochord and somite evagination from archenteron roof, and egression of ventral mesoderm from somites, in Branchiostoma. Cross-sections, dorsal to the top. (B-B′) Dorsal and ventral mesoderm internalization in urodeles and lampreys. Sagittal sections through early (B) and late (B′) gastrulae, dorsal to the right. (B″) Notochord evagination from archenteron roof in neurula of urodele embryo. (C) Surface mesoderm ingression contributes cells to deep-layer notochord in Xenopus. (D-D″) Zebrafish gastrulation. (D) Late blastula fate map, animal pole to the top, dorsal to the right. (D′) Early gastrula; EVL, enveloping layer. (D″) Late gastrula. yc, syncytial yolk cell. (D‴) Formation of forerunner cells. Prospective forerunner cells in the dorsal marginal EVL (yellow) ingress and move vegetally (reddish) in front of the chordamesoderm, to eventually join the notochord. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
	Fig. 4. Xbra and mesoderm development in Xenopus. (A) Gene expression and fate of early gastrula regions. Higher magnification of dorsal blastopore region at the right. Sagittal sections, dorsal to the right. CM, chordamesoderm; EN, endoderm; LEM, leading edge mesendoderm; LPM, lateral plate mesoderm; PAM, paraxial mesoderm; PCM, prechordal mesoderm; SM, surface mesoderm. (B) Early and (B′) late gastrula Xbra expression in the mesodermal mantle. Dashed red line, approximated, hypothetical anterior limit of initial Xbra expression; black dots, paraxial mesoderm; dashes, chordamesoderm. (C,C′) Gastrulation movements of the mesoderm. Red arrows, involution; red double-arrows, convergent extension; green arrows, spreading and migration of mesoderm. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
	Fig. 5. Overlapping expression of Xbra with transcription factors of adjacent tissues. (A) Dorsal marginal zone region at initial (top) and early-to-mid gastrula (bottom). Anterior to posterior (initially: approximately vegetal to animal) sequence from left to right. Inhibitory interactions are indicated. (B) Ventral marginal zone region at mid-early (top) and late gastrula (bottom). NE, neural ectoderm; CNH, chordoneural hinge; BCR meso, BCR mesoderm; otherwise, colors and abbreviations as in Fig. 4. (For interpretation of the references to color in this figure legend, the reader is referred to the online version of this chapter.)
	Fig. 6. Topology of germ layers in deuterostomes. (A) In sea urchins, brachyury (bra; outlined in pink) is expressed in the ectoderm at its boundary to the endoderm. Ancestral, non-chordate mesoderm at the vegetal pole is isolated from the ectoderm by endoderm. (B) Hypothetical intermediate stage where the ancestral mesoderm has been shifted to the dorsal ectoderm boundary, and part of the ectoderm is being recruited to the mesoderm (dashed red lines) through brachyury (dashed pink lines). Neural ectoderm (dashed dark blue line) forms adjacent to this novel, chordate-specific chordamesoderm and paraxial mesoderm. (C) These changes generate the Branchiostoma germ layer arrangement, with the ancestral non-chordate mesoderm having become the lateral plate mesoderm. (D) Ventral expansion of ancestral and novel mesoderm separates the endoderm from the ectoderm. A multipotent progenitor cell population persists at the ectoderm-mesoderm boundary where sox2 and bra overlap. Mixl1/draculin and sox17 define lateral plate mesoderm and endoderm, respectively. Animal is to the top, vegetal to the bottom, dorsal to the right, and ventral to the left. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
	Fig. 7. Larval phenotype of Xbra/Xbra3 loss-of-function. (A,A′) Swimming larvae developed from control (A) and Xbra/Xbra3 knockdown embryos (A′). (B,B′) Cross-sections of larvae at levels shown by vertical lines in (A,A′).
	Fig. 8. Brachyury-controlled transcription factor network in paraxial mesoderm. Red, brachyury (Xbra/Xbra3) and activated direct brachyury target genes; blue, inhibited direct brachyury target genes. Horizontal brackets, self-maintaining redundant control modules. Empty arrows, interactions between modules; filled arrows, interactions between genes. Simplified network stressing interaction between modules, and early gastrula role of myogenic module in somite formation and neural inhibition, late role in muscle formation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
	Fig. 9. Peak involution of dorsal mesoderm and early gastrula lineage segregation. (A-A‴) Normal development. (A-A′) Early to mid-early gastrula, with Gsc domain (orange) having started to internalize. (A′) to (A″) rapid involution of Xbra domain (red, curved arrow). (A‴) Chordin marker expression (grey) in chordamesoderm in form of a gradient, with minimum at blastopore lip. A normal archenteron (arc) has formed, and the chordamesoderm is separated from neural ectoderm by Brachet's cleft. Sagittal sections, dorsal to the right. (B-B‴) Corresponding stages from Xbra loss-of-function embryos. Note temporary absence of Xbra expression in (B′). Asterisks in (A-A″, B-B″), prospective tip of blastopore lip after peak involution. (B‴) Chordin expression no longer increases from the blastopore lip to anterior; archenteron is short; and Brachet's cleft is absent posteriorly. (C,D) A burst of early neural-mesodermal lineage segregation depends on EphA4-induced Xbra expression, which inhibits neural and promotes chordamesoderm and paraxial mesoderm fates (C). If EphA4 function is blocked (D), Xbra is temporarily downregulated, most of the posterior mesoderm becomes partially neutralized (compare C′ and D′, respectively), and trunk and tail somite and notochord formation (C″) is attenuated (D″). Earlier, gastrulation is secondarily affected. Formation of Brachet's cleft (A‴) and peak involution (A″) as well as the parallel convergent extension of chordamesoderm (green double arrow) and neural ectoderm (yellow double arrow) (C′) which occur at different rates (length of double arrows) are diminished (B″), (orange double arrow in D′). Blue, neural ectoderm; red, chordamesoderm and paraxial mesoderm; orange, prechordal mesoderm; magenta in (C″,D″), somite-derived muscle. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)