Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development.
The Drosophila sine oculis homeobox-containing gene is known to play an essential role in controlling the initial events of pattern formation in the eye disc and is also required for the development of other parts of the fly visual system including the optic lobes. In this paper, we report the isolation of a sequence-related gene referred to as Six3. Based on its amino acid sequence, this gene can be included in the new Six/sine oculis subclass of homeobox genes. Early on, Six3 expression is restricted to the anterior neural plate including areas that later will give rise to ectodermal and neural derivatives. Later, once the longitudinal axis of the brain bends, Six3 mRNA is also found in structures derived from the anterior neural plate: ectoderm of nasal cavity, olfactory placode and Rathke's pouch, and also the ventral forebrain including the region of the optic recess, hypothalamus and optic vesicles. Based on this expression pattern, we conclude that Six3 is one of the most anterior homeobox gene reported to date. The high sequence similarity of Six3 with the Drosophila sine oculis, and its expression during eye development, suggests that this gene is the likely murine homologue. This finding supports the idea that mammals and insects share control genes such as eyeless/Pax6 (Halder, G., Callaerts, P. and Gehring, W. J. (1995) Science 267, 1788-1792), and also possibly other members of the regulatory cascade required for eye morphogenesis. In Small eye (Pax6) mouse mutants Six3 expression is not affected. Finally, based on the chromosomal localization and the expression pattern of the mouse Six3 gene, the human Six3 cognate could be a good candidate to be at least one of the genes affected in patients with holoprosencephaly type 2 due to an interstitial deletion of 2p21-p22. This region shares a homology with the distal region of mouse chromosome 17 where Six3 has been mapped.