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Pownall ME, Isaacs HV. FGF Signalling in Vertebrate Development. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

Cover of FGF Signalling in Vertebrate Development

FGF Signalling in Vertebrate Development.

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Segmentation of the vertebrate body is driven by the regular repeated formation of somites from the paraxial presegmental (or presomitic) mesoderm (PSM). Somites are transient mesodermal structures that form as balls of epithelial cells from the anterior part of the PSM and will give rise to the vertebrae and ribs as well as all of the skeletal muscle in the body and the dermis of the skin. In addition to forming the overtly segmented vertebrae, the somites also provide extracellular guidance cues for migrating neural crest and axons, which means that somitogenesis also underpin the segmented pattern of the nervous system.

The process of somitogenesis passes through the embryo in an anterior to posterior wave where somites form one pair at a time with a clock-like rhythm. There is evidence for an internal oscillator that regulates this process and several genes downstream of Notch signalling have been identified as having a rhythmic expression pattern in time with somite formation. In the chick PSM, the expression of the genes cHairy-1(Hes1) and lunatic fringe (among others) cycle in time with the formation of a pair of somites. Related genes are also known to cycle in mouse, fish, and frog embryos indicating that this molecular mechanism is conserved in vertebrates (Dequeant and Pourquie, 2008).

Somite segmentation is coupled to the posterior extension of the body axis. In the posterior of amniote embryos, cells continue to be produced and move through the primitive streak. These cells are present in the posterior PSM as loosely associated mesenchyme and as they move towards the anterior, they organise into an epithelium to form the somitomeres, which are presumptive somites. There is a transition point in the PSM along the anteroposterior axis where cells begin to form somitomeres; this is called the determination front. The determination front is manifest by the expression of a bHLH gene called Mesp2 (thylacine) in the anterior three somitomeres, marking future somite boundaries (Oginuma et al., 2008). The determination front moves in a posterior direction like a wave as the axis of the embryo elongates in an anterior to posterior direction.

A clever microarray analysis has identified FGF signalling as a key component the pathway regulating somitogenesis. In this study, individual PSM explants were excised and processed on chips, after which they were retrospectively assigned to a particular phase of the somitogenic cycle by assessing the expression lunatic fringe in the remaining embryo (Dequeant et al., 2006). Genes downstream of FGF were activated with a distinct expression profile during somite segmentation. FGF8 is expressed at high levels in the posterior PSM and has been shown to keep the posterior PSM cells in an immature state (Delfini et al., 2005). Activating FGF signalling by electroporating constitutively active MEK plasmids into chick PSM was used to manipulate the FGF signalling pathway. Using time-lapse video microscopy, it was demonstrated that cells with high levels of MAPK activity maintain high motility that is characteristic of the cells normally present in the posterior PSM, while cells in the anterior PSM normal are less motile as they undergo MET to form a somitomere. The role of FGF in maintaining cells in an immature, undifferentiated state in the tailbud is not restricted to the PSM cells, as neural precursor have also been found to require a reduction in FGF signalling before they will differentiate (Diez del Corral et al., 2002). Ectopic FGF ligand also interferes with segmentation (Dubrulle et al., 2001) as demonstrated when PSM exposed to a bead soaked with FGF8 gives rise to irregular-sized somites. Furthermore, conditional knockouts of FGF-R1 in the posterior mesoderm results in mice with large, irregular somites that give rise to fused vertebrae and irregular vertebrae and ribs (Wahl et al., 2007).

A working model to explain these results is illustrated in Figure 12. High levels of posterior FGF decreases anteriorly, creating a gradient of FGF activity in the PSM. Below a critical threshold level of FGF signalling is the determination front marked by the expression of Mesp2 and the formation of somitomeres. One important aspect of this model is that posterior FGF is opposed by the anterior signal RA. Indeed, FGF and RA have been found to be mutually inhibitory in both the PSM (Moreno and Kintner, 2004) and the neuroepithelium (Diez del Corral et al., 2003). When the FGF pathway is activated by constitutively active MEK, the expression of the RA-synthesising enzyme raldh is inhibited. Moreover, the expression of cyp26 (a P450 enzyme that metabolizes RA) is ablated in embryos lacking FGF. These data indicate that FGF signalling represses raldh expression and is required for cyp26 expression and this is how FGF negatively regulates RA biosynthesis. Experiments treating embryos with chemical inhibitors of FGF furthermore support the notion that RA represses FGF. In this way, the positioning of somite boundaries at the determination front is established (Moreno and Kintner, 2004). More evidence that an FGF gradient is important for determining where the transition from PSM to segmented somite occurs comes from studies on two cell-autonomous inhibitors of FGF signalling, Shisa2 (Nagano et al., 2006) and Sulf1 (Freeman et al., 2008). The genes that code for both of these regulators are expressed in the paraxial mesoderm anterior to FGF8 expression. Knockdown of either Shisa2 or Sulf1 in Xenopus results in an anterior shift of dpERK activity and a corresponding anterior shift in Mesp2 (thylacine) expression. Shisa acts to trap the FGFR in the endoplasmic reticulum (Yamamoto et al., 2005), while Sulf1 discourages the formation of the FGF signalling complex at the cell surface (Wang et al., 2004). These studies show that such factors within cells reduce the level of signal that is perceived, lowering the effective level of FGF signalling at the determination front. These factors contribute to the local level of FGF activation, and it has been shown that interference with these regulators changes where somites will form (Freeman et al., 2008; Nagano et al., 2006).

FIGURE 12. A posterior to anterior gradient of FGF establishes the determination front.


A posterior to anterior gradient of FGF establishes the determination front. There is a high level of FGF signalling in the posterior mesoderm; this is opposed by RA signalling that is present in the somites. FGF promotes the motile undifferentiated nature (more...)

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53154
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