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Evolutionarily conserved developmental pathways

Tissue patterning and boundary formation: a role for Fringe in modulating Notch signaling

The involvement of Fringe (Fng) in boundary formation and the potential role of Fringe in establishing symmetry patterns during development constitutes an evolutionarily conserved developmental pathway. In Drosophila, Fringe has been shown to modulate Notch signaling; this results in the formation of a border between dorsal and ventral cells in the wing. Fringe is similarly involved in establishing a border between dorsal and ventral domains in the Drosophila eye. In a similar fashion, the gene Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb.

During wing development in Drosophila, Fringe (through a cell-autonomous mechanism) inhibits a cell's ability to respond to Serrate (Ser) protein and potentiates its ability to respond to Delta (Dl) protein. Activation of Notch receptor along the border between dorsal and ventral cells leads to the specification of specialized cells that express Wingless (Wg) and organize wing growth and patterning. Three genes, fringe, Serrate and Delta, are involved in the cellular interactions leading to Notch activation. The relationships among these genes during the development of the Drosophila wing have been investigated by a combination of expression and coexpression studies. Ser is normally expressed in dorsal cells while Dl is initially expressed by all wing cells. However, their expression soon becomes restricted to the dorso-ventral boundary. Ser and Dl induce and maintain one another's expression through a positive feedback loop. Importantly, their ability to induce each other's dorsal-ventral expression is asymmetric: Ser induces Dl strongly in ventral cells, but only very weakly in dorsal cells; Dl induces Ser expression in dorsal cells, but not in ventral cells. fng is expressed specifically by dorsal cells and functions to position and restrict this feedback loop to the developing dorsal-ventral boundary (Panin, 1997).

D-V signaling in the eye shares many similarites with D-V signaling in the wing. In the Drosophila eye, specialized cells are established along the dorsal-ventral midline by Notch-mediated signaling between dorsal and ventral cells. In the case of both eye and wing, an initial asymmetry is set up by Wingless expression. Cells then go through a distinct intermediate step: in the wing, Wingless represses Apterous, a positive regulator of fringe expression; in the eye, Wingless promotes the expression of mirror (mrr), which encodes a negative regulator of fringe. Cells in both the eye and the wing then share a Fng-Ser-Dl-Notch signaling cassette to effect signaling between dorsal and ventral cells and establish Notch activation along the D-V midline. Local activation of Notch in eye and wing leads to production of diffusible, long-range signals that direct growth and patterning: in the wing, these signals include Wingless, but in the eye they remain unknown (Papayannopoulos, 1998).

In vertebrates, the gene Radical fringe positions the apical ectodermal ridge (AER) at the dorsoventral boundary of the vertebrate limb. R-fng is homologous to Drosophila fng. Weak but significant similarity of Fng proteins to the Lex1 family of biosynthetic enzymes suggests that R-fng may function as a glycosyltransferase. This homology indicates that R-fng may operate through the recognition, and perhaps modification, of carbohydrate moieties linked to either extracellular proteins or lipids. R-fng is expressed in the dorsal ectoderm and apical ectodermal ridge prior to the expression of Fgf-8, a gene thought to play a role in the formation of the AER. Abnormal limb phenotypes consisting of AER-like structures are observed in 16% of embryos infected with a replication-competent retroviral vector containing R-fng, suggesting that R-fng misexpression perturbs the normal formation of the AER. Engrailed-1 (see Drosophila Engrailed), normally expressed in the ventral ectoderm, strongly represses R-fng, suggesting that En-1 regulates dorsal-ventral polarity of the limb and the positioning of the AER. This En-1 role contrasts with the role taken by Engrailed in Drosophila: the regulation of posterior compartment identity. It is suggested that the AER develops at the interface of two adjacent tissue types: tissue expressing high levels of R-fng and tissue that does not express R-fng. Because R-fng is not normally expressed on the ventral side of the limb, ectopic expression of R-fng here creates new boundaries that result in additional AERs. Serrate-2 (see Drosophila Serrate) is expressed in the AER from the earliest stages of its formation through at least stage 26. Chicken Notch-1 is also expressed in the AER. Thus R-fng, like its Drosophila counterpart, may act upstream of Notch signaling (Laufer, 1997 and Rodriguez-Esteban, 1997).


Laufer, E., et al. (1997). Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature 386: 366-373. PubMed Citation: 9121552

Panin, V. M., et al. (1997). Fringe modulates Notch-ligand interactions. Nature 387(6636): 908-912. PubMed Citation: 9202123

Papayannopoulos, V., et al. (1998). Dorsal-ventral signaling in the Drosophila eye. Science 281(5385): 2031-4. PubMed Citation: 9748163

Rodriguez-Esteban, C., et al. (1997). Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature 386: 360-366. PubMed Citation: 9121551

date revised: 15 December 98

Developmental Pathways conserved in Evolution

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