Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace(fgf8) and coincident defects in CNS development

During the development of the zebrafish nervous system both noi, a zebrafis h pax2 homolog, and ace, a zebrafish fgf8 homolog, are required for develop ment of the midbrain and cerebellum. Here we describe a dominant mutation, aussicht (aus), in which the expression of noi and ace is upregulated, In a us mutant embryos, ace is upregulated at many sites in the embryo, while It oi expression is only upregulated in regions of the forebrain and midbrain which also express ace. Subsequent to the alterations in noi and ace expres sion, aus mutants exhibit defects in the differentiation of the forebrain, midbrain and eyes. Within the forebrain, the formation of the anterior and postoptic commissures is delayed and the expression of markers within the p retectal area is reduced. Within the midbrain, En and wnt1 expression is ex panded. In heterozygous aus embryos, there is ectopic outgrowth of neural r etina in the temporal half of the eyes, whereas in putative homozygous aus embryos, the ventral retina is reduced and the pigmented retinal epithelium is expanded towards the midline, The observation that ans mutant embryos e xhibit widespread upregulation of ace raised the possibility that aus might represent an allele of the ace gene itself. However, by crossing carriers for both aus and ace, we were able to generate homozygous ace mutant embryo s that also exhibited the aus phenotype, This indicated that aus is not tig htly linked to ace and is unlikely to be a mutation directly affecting the ace locus. However, increased Ace activity may underly many aspects of the aus phenotype and we show that the upregulation of noi in the forebrain of aus mutants is partially dependent upon functional Ace activity. Conversely , increased ace expression in the forebrain of arcs mutants is not dependen t upon functional Noi activity. We conclude that aus represents a mutation involving a locus normally required for the regulation of ace expression du ring embryogenesis.