Patterning without morphogenesis in medaka eye mutant

Vertebrate eye formation starts during gastrulation with the determination of an eye field in the anterior ectoderm. Subsequently well-coordinated inductive events lead to the formation of a single retinal primordium in the anterior neuroectoderm and the presumptive lens placodes in the abutting head ectoderm (for review see Grainger, 1996; Jean et al., 1998). At late gastrula/early neurula stages, this single retinal field is split into two bilateral symmetrical retinal primordia by cell movements under the influence of signals emanating from the ventral midline (Gritsman et al., 1999; Li et al., 1997; Varga et al., 1999). Morphogenesis during neurula stages results in the evagination of the optic vesicles from the lateral wall of the forebrain, a process that requires changes in cell proliferation and programmed cell death (Schmitt and Dowling, 1994). Concomitantly, lens specification occurs when the optic vesicle contacts the overlying ectoderm of the lens placode (reviewed in Grainger, 1996). The optic vesicles invaginate under the influence of the developing lens to form the optic cups, in which differentiation of the neuroretina and the pigmented retinal epithelium (PRE) starts. The optic cup remains attached to the ventral diencephalon by the optic stalk, which eventually serves as a leading track for the projection of retinal axons to target regions in the midbrain. Insect eye development has been analysed by a combination of genetic and molecular techniques. Surprisingly, key players, acting high up in the genetic pathway controlling Drosophila eye development, were found to be evolutionary conserved (Halder et al., 1995; Hammond et al., 1998; Oliver et al., 1995; Quiring et al., 1994; Xu et al., 1997) and to exert a comparable function during vertebrate eye development (Hill et al., 1991; Loosli et al., 1999; Oliver et al., 1996; Ton et al., 1991). In homozygous Small eye (Sey) mouse and rat, mutations in the transcription factor Pax6 lead to the complete absence of the eyes, including lens, and the nose (Hill et al., 1991; Hogan et al., 1986; Matsuo et al., 1993). In these embryos, the optic vesicles initially evaginate, but degenerate during subsequent stages of development (Hogan et al., 1986). Recently, it was shown that overexpression of Pax6 mRNA in Xenopus embryos can lead to the formation of an ectopic eye (Chow et al., 1999). Six3, a homeobox gene, is expressed early in the anterior neuroectoderm and subsequently in the optic vesicles and prosencephalon (Bovolenta et al., 1998; Kobayashi et al., 1998; Loosli et al., 1998; Oliver et al., 1995; Seo et al., 1998). Overexpression of Six3 mRNA in medaka initiates the formation of ectopic retina tissue in the midbrain and anterior hindbrain involving a regulatory interaction of Six3 and Pax6 (Loosli et al., 1999). This indicates a role for Six3 and Pax6 in early steps of vertebrate retina formation. Targeted inactivation of the transcription factor Rx in mouse results in the absence of eye structures and in severe defects of the anterior forebrain, demonstrating the necessity of this gene for eye development (Mathers et al., 1997). Mice lacking sonic hedgehog gene function exhibit cyclopia phenotypes, demonstrating an involvement of sonic hedgehog in the early proximodistal patterning of the retinal primordia (Chiang et al., 1996), as also suggested by overexpression experiments in fish embryos (Ekker et al., 1995; Macdonald et al., 1995). Mutations affecting eye development have been isolated in 1911 Development 127, 1911-1919 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV2526