Eye Development: Governed by a Dictator or a Junta?

The fly and vertebrate eyes are obviously very different, and evolutionary studies have suggested that eyes have independently appeared multiple times throughout evolution (Salvini-Plawen and Mayr 1977xSalvini-Plawen, L.V and Mayr, E. Evol. Biol. 1977; 10: 207–263See all ReferencesSalvini-Plawen and Mayr 1977). Thus, unique sets of genes might have been expected to direct the differentiation of these various types of eyes. Still, mutations in the Pax6 genes of flies, mice, and humans all lead to loss of eyes (Strachan and Read 1994xStrachan, T and Read, A.P. Curr. Opin. Genet. Dev. 1994; 4: 427–438Crossref | PubMed | Scopus (191)See all ReferencesStrachan and Read 1994). To explain why the same gene is controlling very different processes, it has been postulated that the initial role of Pax6 was to regulate photoreceptor differentiation in a primitive “eye” formed only of photoreceptors (18xZuker, C.S. Science. 1994; 265: 742–743Crossref | PubMedSee all References, 15xSheng, G, Thouvenot, E, Schmucker, D, Wilson, D.S, and Desplan, C. Genes Dev. 1997; 11: 1122–1131Crossref | PubMedSee all References). As the optical structures of the eye evolved differently in various species, the same regulator was co-opted for each upstream stage of development. In support of this model, ey is not only expressed in the embryonic eye primordium and in the developing eye disc, but is re-expressed at the time of photoreceptor terminal differentiation. This terminal phase of ey function is likely to represent its ancestral role, which is to control expression of the rhodopsin genes through a highly conserved binding site that is found in the rhodopsin promoters of most species (Sheng et al. 1997xSheng, G, Thouvenot, E, Schmucker, D, Wilson, D.S, and Desplan, C. Genes Dev. 1997; 11: 1122–1131Crossref | PubMedSee all ReferencesSheng et al. 1997). It is now becoming clear that, in fact, an entire genetic cassette may be used for eye development in many species. Homologs of so, eya, and dac have been described in vertebrates (6xChen, R, Amoui, M, Zhang, Z, and Mardon, G. Cell. 1997; 91: 893–903Abstract | Full Text | Full Text PDF | PubMed | Scopus (298)See all References, 12xOliver, G and Gruss, P. Trends Neurosci. 1997; 20: 415–421Abstract | Full Text | Full Text PDF | PubMed | Scopus (92)See all References), and they often appear to have overlapping expression patterns in the eye and elsewhere, supporting the model that a molecular complex forms between their gene products. Interestingly, the protein domains that mediate protein–protein contacts between so, eya, and dac are conserved in their vertebrate counterparts. However, as no mutations in genes other than Pax6 exist in vertebrates, the only functional data so far come from studies in amphibians and fish where ectopic expression of both Pax6 and six-3, a so homolog expressed in the eye, can specify ectopic lens fate, but not retinal fate (3xAltmann, C.R, Chow, R.L, Lang, R.A, and Hemmati-Brivanlou, A. Dev. Biol. 1997; 185: 119–123Crossref | PubMed | Scopus (134)See all References, 12xOliver, G and Gruss, P. Trends Neurosci. 1997; 20: 415–421Abstract | Full Text | Full Text PDF | PubMed | Scopus (92)See all References). Furthermore, although ey regulates so in Drosophila, six-3 expression is independent from Pax6 in mice, suggesting that the epistasis is different in different species. Confirmation that there is a conserved gene cassette for eye development awaits loss-of-function analyses through the generation of mice mutant for these genes. However, as the expression pattern of all of these genes is much broader than just the eye, it is likely that the specific function of each gene will depend on a combinatorial mechanism.These results highlight the power of gain-of-function approaches as a way to decipher a complex set of pathways constructed of multiple interactions that classical loss-of-function experiments have problems identifying. Similarly, gain-of-function experiments in Xenopus have been able to induce a new “organizer” in the early embryo and induce axis duplication (“twinning” of the embryo, a transformation that is even more dramatic than eye induction!). Using injection of mRNA encoding signaling molecules or putative transcriptional regulators, these experiments have produced a precise description of interacting signaling pathways (e.g., Wnts and BMPs) and of their role in axis formation during early vertebrate development. In conclusion, multiple genes can activate the eye development pathway, which does not appear to be a simple linear cascade controlled by a master regulator gene. The epistatic relationship may in fact be only required to ensure that the entire cascade of genes is expressed, while their action may involve regulatory loops involving protein–protein contacts. While ey still appears to play the most critical role, its function in multiple stages of eye development (or elsewhere), perhaps in all organisms, clearly requires the combinatorial action of other key regulatory genes.