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The forebrain is the most anterior portion of the central nervous system and gives rises to the telencephalon, diencephalon, and the eyes during development. All derivatives of the forebrain originate from the anterior neural plate. Therefore, mutations in genes that disrupt forebrain development provide a powerful tool for dissecting the mechanisms that regionalize the neural plate, establish fate restrictions, and determine the identities of all its main derivatives including the eyes.
In humans, mutations in the SIX3 gene encoding a homeodomain transcription factor have been associated with holoprosencephaly, the most common embryologic malformation of the forebrain in humans. The functional inactivation of Six3 in mice allowed us to determine that Six3 is a crucial regulator of vertebrate head development; its activity is essential to regulate key molecular events required for the regional patterning of the anterior neural plate.
The generated Six3 mutant mice lack the rostral forebrain and we determined that Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development (Lagutin et al., 2003).
Following the specification of the anterior neural plate, the optic vesicles evaginate from the ventral forebrain to produce the lens and retina of the vertebrate eye.
Six3 expression in the developing eye suggested that most likely it is also an important regulator of the early stages of visual system development in vertebrates. This proposal was corroborated by the conditional deletion of mouse Six3 in the eye field. Using this approach we showed that neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate. Using chromatin immunoprecipitation assays (ChIP), we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly represses Wnt8b expression in vivo.