Zebrafish Hairy/Enhancer of split protein links FGF signaling to cyclic gene expression in the periodic segmentation of somites

Abstract

Notch and fibroblast growth factor (FGF) signaling pathways have been implicated in the establishmentSomites are the morphologically distinct segmental units that are transiently formed during early vertebrate development and subsequently give rise to metameric and fundamental structures such as the vertebrae of the axial skeleton, their associated muscles, and tendons. The somites are subdivided from the anterior end of the unsegmented paraxial mesoderm, called the presomitic mesoderm (PSM), and sequentially generated in an anterior to posterior direction in a rhythmic fashion at regular spatiotemporal intervals. The molecular mechanism underlying the periodical formation of somites is coupled to an internal oscillator, referred to as the "segmentation clock", which has been evidenced by the cyclic expression of genes in the PSM (Palmeirim et al. 1997;Maroto and Pourquie 2001). Most genes that exhibit a cyclic expression pattern in the PSM are involved in the Notch signaling pathway . Various hairy/Enhancer of split (Espl)-related basic helix-loop-helix (bHLH) genes (hairy-1, hairy-2, and Hey2 in the chicken; Hes1, Hes5, Hes7, and Hey2 in the mouse; her1 and her7 in the zebrafish) that are transcriptional targets of the Notch signaling are expressed in a dynamic pattern of stripes across the PSM in a posterior to anterior direction. In addition, Lunatic fringe, encoding a glycosyltransferase that modulates the Notch signaling in the chicken and mouse, and the Notch ligand deltaC in the zebrafish also show an oscillatory expression pattern in the PSM. These cyclic genes, as well as other components of the Notch signaling pathway, were shown to be required for the proper somite segmentation in mice ( The oscillating and anteriorly propagating wave of gene expression, which is maintained in the posterior PSM, becomes fixed to cause segmentation in the anterior PSM. Activity gradients of signaling molecules, including fibroblast growth factor (FGF), Wnt, and retinoic acid are proposed to regulate the differentiation of PSM cells along the anteroposterior axis from a state permitting the oscillating gene expression to a state driving the segmentation program (Dubrulle et al. 2001;Sawada et al. 2001;Aulehla et al. 2003;Moreno and Kintner 2004). For instance, FGF signaling is the highest at the posterior end of the PSM with a gradual decrease toward the anterior, suggesting a role for FGF signaling in maintaining the characteristics of the posterior PSM cells (Dubrulle et al. 2001;Sawada et al. 2001). In fact, overexpression of FGF8 in the entire PSM of chick embryos causes an increase in the expression of Brachyury in the posterior PSM and suppresses morphological segmentation (Dubrulle et al. 2001). Furthermore, transient activation or inhibition of FGF signaling results in the formation of smaller or larger somites, respectively. Thus, FGF signaling appears to maintain the posterior characteristics, which allows the cyclic gene expression, and the level of FGF activity regulates the transition of the posterior PSM ...

Tbx6-mediated Notch signaling controls somite-specific Mesp2 expression

“…The involvement of RA in Mesp2 expression remains elusive, however, because the disruption of CYP26 (37), a degradation enzyme for RA, does not severely affect Mesp2 expression levels (2). In the zebrafish embryo, FGF signaling up-regulates a basic helixloop-helix transcription factor, her13.2, which maintains the oscillation of the Notch signals in both the tailbud and PSM by repressing the Notch-regulated genes her1 and her7 (38). RA and Fgf signals may thus contribute to the positioning of Mesp2 expression by coordinating the regular oscillation of Notch signals in the tailbud and PSM.…”

The genetics and embryology of zebrafish metamerism

“…Loss of her1 in combination with loss of other genes can perturb all somites. References: a , b (Sawada et al, 2000), c (Holley et al, 2002), d (Henry et al, 2002), e (Oates and Ho, 2002), f , g (Sieger et al, 2004), h , i , j , k (Pasini et al, 2001), l (Pasini et al, 2004), m (Oates et al, 2005a), n (Shankaran et al, 2007), o (Kawamura et al, 2005b), and p (Winkler et al, 2003).…”

“…3; Gajewski et al, 2006), while Her13.2 should be coexpressed with them throughout the posterior tail bud ( Fig. 3; Kawamura et al, 2005b). Her11 should overlap with the other oscillating Her proteins in the anterior and posterior PSM.…”

Segmental border is defined by the key transcription factor Mesp2, by means of the suppression of notch activity

“…The link between FGF and Notch signaling is also indicated in zebrafish. A Hes family gene Her13.2 has been shown to be activated by FGF in the PSM, and Her13.2 and Her1 generate a heterodimer complex to suppress her1 transcription, which results in the generation of her1 oscillation (Kawamura et al, 2005). This relationship represents a link between FGF and the segmentation clock.…”