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First published online April 24, 2009
doi: 10.1242/10.1242/dev.021246

Development 136, 1591-1604 (2009)
Published by The Company of Biologists 2009
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Stem cells, signals and vertebrate body axis extension

Valerie Wilson1, Isabel Olivera-Martinez2 and Kate G. Storey2,*

1 Institute for Stem Cell Research and MRC Centre for Regenerative Medicine, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JQ, UK.
2 Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.


Figure 1
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  		Fig. 1. Transverse section through a typical vertebrate embryo. Schematic showing the stereotyped positions of key tissues in a vertebrate embryo. The central neural tube (nt, blue) is flanked by somitic mesoderm (s, green), and below the embryo's ventral midline is the notochord (nc, purple), an axial mesodermal tissue that lies above the aorta (a, red), gut (g, grey), veins (v, yellow), and nephric tubules (ntb, orange). A covering of surface ectoderm/epidermis (e, dark green) encases all of these tissues.

 

Figure 2
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  		Fig. 2. Location of key tissues and caudal progenitor cell populations in mouse and chick embryos. (A-D') Schematics showing the location of key tissues in (A,B) early (six somites; mouse E8.5, chick HH8) and (C-D') late (35 somites; mouse E10.5, chick HH18) embryos. At the six-somite stage, the primitive streak (PS), node (N), notochord (NC), neural tube (NT) and somites (S) are visible in both (A) mouse and (B) chick embryos. Regions that contribute to the extending body axis, namely the node-streak border (NSB) and caudal lateral epiblast (CLE), are also indicated. (C-D') Both of these cell populations also contribute to the later-forming chordo-neural hinge (CNH; red box) located in the tail bud (TB; blue box) at the junction of the notochord and neural tube, and rostral to the tail bud mesoderm (TBM). C' and D' represent longitudinal sections through the tail bud. C, caudal; E, embryonic day; R, rostral.

 

Figure 3
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  		Fig. 3. Possible mechanisms for generating the body axis. Putative stem cell and non-stem cell mechanisms to generate axial tissues. (A) Separate populations of cells that generate discrete portions of the axis, and whose births predate axial extension, could generate the spinal cord. (B) Alternatively, stem cells present throughout axial elongation could continue to generate axial tissue. Different colours represent different clonally-derived populations. The embryo diagrams show the eventual position of the cells that are depicted schematically below the embryo. Upper row of cells, progenitors (stem cell or non-stem cell); lower row of cells, differentiated derivatives at their final axial destination.

 

Figure 4
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  		Fig. 4. Predicted patterns of axial tissue contribution from candidate parent populations by retrospective clonal analysis. Schematic of the predicted patterns of contribution to the axis arising in clones originating from either axial stem cells or transient progenitors, as seen by retrospective clonal analysis in developing mouse embryos. Adapted, with permission, from Nicolas et al. (Nicolas et al., 1996Go). (A) Pattern expected from a single recombination event in a stem cell that contributes to somites. The progenitor region is shown as consisting of three hypothetical compartments, one containing stem cells (dark pink circles), and two, on either side of the midline, containing transient progenitors (light pink circles). The latter might in reality include, but not be limited to, the presomitic mesoderm. Arrows represent cell movements and concurrent differentiation events from stem cell to transient progenitor to differentiated somites. If a laacZ-to-lacZ reversion event occurs in a stem cell during axis elongation (blue circle), its descendants will exit first to the transient progenitor compartment, and from there to the somites. Stripes represent a situation where a stem cell and its descendants are members of a population and therefore contribute only a fraction of the total cell number of a somite. During development, if a stem cell remains in the progenitor region for long periods, it can in principle contribute descendants to all axial levels formed by the population after the reversion event. (B) When a large group of clones label the myotome (represented without the progenitor region to show that only the differentiated somite is labelled) the diagnostic test for whether a stem cell population has contributed to the somite is that large clones will have a variable rostral limit, corresponding to the time of initiation of the clone, and a caudal limit at the caudal-most end. (C) By contrast, transient progenitor-derived clones will label smaller stretches of somites. (D) Transient progenitor-derived clones, which would initiate at random and are by definition not retained in the progenitor region, are not expected to show the polarised pattern seen in B.

 

Figure 5
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  		Fig. 5. Defining the node-streak border, caudal lateral epiblast and chordo-neural hinge. (A,B) Schematics of (A) mouse and (B) chick 2- to 6-somite (Aa,Ba) and 35- to 40-somite (Af,Bf) embryos, depicting the node and the tail bud regions (blue boxes) shown below. (Ab-Ad,Ag-Ai,Bb-Bd,Bg-Bi) Whole-mount in situ hybridisation of selected genes expressed in the node-streak border (NSB, red boxes in early embryos) and chordo-neural hinge (CNH, red boxes in late embryos): Bra (Ab,Ag,Bb,Bg); Foxa2 (Ac,Ah,Bc,Bh) and Fgf8 (Ad,Ai,Bd,Bi). Ab and Bb, ventral view; Ac,Ad,Ag-Ai,Bc,Bd,Bg-Bi, sagittal sections. Both Bra and Fgf8 are expressed in the NSB and the CNH in both species, but their expression extends further rostrally in the chick than in the mouse. Thus, in the chick, they cannot be considered markers of the NSB or CNH. Foxa2 labels the end of the neural tube and notochord in both species and can be used to localise the NSB and the CNH. (Ae,Aj,Be,Bj) Summary diagrams showing the similar topography of Foxa2 (dark red) and Fgf8 (orange) gene expression in the mouse and chick NSB and CNH. C, caudal; N, node; NC, notochord; NT, neural tube; PS, primitive streak; TBM, tail bud mesoderm; R, Rostral.

 

Figure 6
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  		Fig. 6. Signals that regulate axis extension in chick and mouse embryos. (A,B) Schematics of the molecular interactions that regulate differentiation in the extending body axis in chick and mouse, with reference to the supporting published data (indicated by the numbers on the schematics and below). (A) In the HH10 chick, Fgf8 inhibits the onset of expression of the retinoic acid (RA)-synthesizing enzyme Raldh2 in the presomitic mesoderm (1) and the expression of Rarb in the neuroepithelium (4), thus preventing RA from triggering differentiation in the CLE and the caudal-most paraxial mesoderm (1,5). In addition, Fgf8 inhibits sonic hedgehog (Shh) expression in the floorplate, controlling the onset of ventral patterning genes (1). FGF signalling is also required for expression of Delta1 in the medial CLE (2) and promotes expression of Wnt8c (4). As Fgf8 decays in the caudal paraxial mesoderm (Dubrulle and Pourquié, 2004Go), Wnt signalling, most likely provided by Wnt8c, now acts to promote Raldh2 in the adjacent presomitic mesoderm (4). RA produced by Raldh2 activity represses Fgf8 (1) and Wnt8c (3,4), and the expression of both these genes is increased in vitamin A-deficient quails (1,4). (B) In the E8.5-E9.5 mouse, Fgf8 is maintained by Wnt3a, as indicated by Fgf8 loss in the Wnt3a hypomorph vestigial tail (14). Loss of signalling through Fgfr1 specifically in the T-expressing domain leads to loss of Cyp26a (13). Loss of such signalling also leads to increased Delta1 expression in the emerging paraxial mesoderm (13). Excess RA signalling by RA treatment (7,8) or loss of Cyp26a (9,10) leads to a reduction of caudal Wnt3a expression. Raldh2 mutant mice exhibit an expanded domain of caudal Fgf8 (11,12,15) and Wnt8a (6). RA is also required for the onset of neuronal differentiation and for expression of patterning genes in the neural axis (15,16). CLE, caudal lateral epiblast; FP, floorplate; N, node; NT, neural tube; PM, paraxial mesoderm; PS, primitive streak; S, somite. References that support the interactions shown: 1 (Diez del Corral et al., 2003Go), 2 (Akai et al., 2005Go), 3 (Dupe and Lumsden, 2001Go), 4 (Olivera-Martinez and Storey, 2007Go), 5 (Novitch et al., 2003Go), 6 (Niederreither et al., 2000Go), 7 (Iulianella et al., 1999Go), 8 (Shum et al., 1999Go), 9 (Sakai et al., 2001Go), 10 (Abu-Abed et al., 2001Go), 11 (Vermot et al., 2005Go), 12 (Sirbu and Duester, 2006Go), 13 (Wahl et al., 2007Go), 14 (Aulehla et al., 2003Go), 15 (Molotkova et al., 2005Go), 16 (Ribes et al., 2008Go).

 

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© The Company of Biologists Ltd 2009