FGF signalling: diverse roles during early vertebrate embryogenesis

Abstract

Fibroblast growth factor (FGF) signalling has been implicated during several phases of early embryogenesis, including the patterning of the embryonic axes, the induction and/or maintenance of several cell lineages and the coordination of morphogenetic movements. Here, we summarise our current understanding of the regulation and roles of FGF signalling during early vertebrate development.

Fig. 1. An overview of FGF signalling

FGF signalling is initiated by ligand-dependent dimerisation of the FGFR, which leads to the cross-phosphorylation (P) of tyrosine residues in the intracellular domain of the receptor tyrosine kinase (not shown). These phosphorylated residues are then bound specifically by several intracellular signal transduction proteins, including PLCγ, FRS2 and Src family members. These initiate several intracellular signalling pathways, including the (A) PLCγ pathway, (B) PI3K/PKB pathway and (C) the Ras/ERK pathway. The cell responses to these different pathways are shown. CamKII, calcium/calmodulin-dependent protein kinase II; DAG, diacylglycerol; ERK, extracellular-signal related kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; FRS2, fibroblast growth factor receptor substrate 2; Gab, Grb2-associated protein; Grb2, growth factor receptor-bound protein 2; HSPG, heparan sulphate proteoglycan; IP₃, inositol (1,4,5)-trisphosphate; MEK, mitogen-activated protein kinase kinase (also known as MAP2K); PI3K, phosphoinositide 3-kinase; PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; PKB, protein kinase B; PKC, protein kinase C; PLCγ, phospholipase C γ; cRaf, v-raf-leukemia viral oncogene homologue 1 (also known as RAF1); Ras, rat sarcoma (also known as Harvey rat sarcoma virus oncogene homologue); SHP2, SH2 domain-containing tyrosine phosphatase 2 (also known as PTPN11); SOS, son of sevenless; Src, sarcoma proto-oncogene tyrosine kinase.

Fig. 2. FGF signalling is necessary for the specification and maintenance of dorsal mesoderm

Fate map of different germ layers at the late blastula/early gastrula stage, along the dorsal-ventral (animal-vegetal) and anterior-posterior (organizer-contra organizer) axes in (A) Xenopus and (B) zebrafish embryos. FGF signalling is high in the animal sector of the marginal zone (red), which is fated to become dorsal axial and paraxial mesoderm, whereas it is low or absent in the vegetal sector of the marginal zone (green in B), which is fated to give rise to ventral mesoderm, such as blood.

Fig. 3. FGF signalling during posterior body axis extension

(A) A schematic of an extending body axis in mouse and chick embryos. In the extreme posterior, FGF signalling is high, maintaining the stem zone at the posterior end of the axis in an undifferentiated state. Retinoic acid (RA) promotes differentiation of neural ectoderm and somitic mesoderm. A gradient of FGF signalling is established, which is antagonised by an inverse gradient of RA signalling. The differentiation front is the position at which RA signalling wins over FGF signalling, resulting in the overt differentiation of neural ectoderm and somitic mesoderm, starting at the transition zone. Neural plate is in purple; undifferentiated presomitic mesoderm (PSM) in orange; differentiated somitic mesoderm in green; and somitic mesoderm in the process of differentiation is shown in overlapping orange and green. (B) These two inverse gradients of FGF and RA signalling are themselves established by Wnt signalling. Note that Wnt8c is induced in the neural plate, whereas FGF8 and Raldh2 are expressed in the mesoderm. Thus, these molecules signal across germ layers. Black lines depict interactions shown in both chick and mouse, red lines are interactions shown in mouse only, and blue are interactions shown in chick only. RARβ, retinoic acid receptor β; Raldh2, retinaldehyde dehydrogenase 2.

Fig. 4. FGF signalling in early cell lineage specification in the mouse embryo

Schematics of mouse embryos at embryonic day (E) 3.25, E3.75 and E4.5. FGF signalling specifies the two first lineages of the mammalian embryo: the trophectoderm, at around the 16- to 32-cell stage; and the primitive endoderm (PrE), at E3.5-4.5. This specification occurs primarily through paracrine induction from the inner cell mass (ICM) and epiblast (EPI), respectively. Meanwhile, FGF signalling must be inhibited within the epiblast to maintain its pluripotency. After implantation, FGF then promotes the overt differentiation of cell types within the epiblast.