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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 presumptive lens ectoderm (PLE) which disrupted lens formation (Liu et al., 2006). In the most severe cases, lens induction and specification were defective, and the lens placode and lens were absent. In Six3- mutant embryos, Pax6 was downregulated, and Sox2 was absent in the lens preplacodal ectoderm. Using ChIP, electrophoretic mobility shift assay, and luciferase reporter assays, we determined that Six3 activates Pax6 and Sox2 expression. Our results positioned Six3 at the top of the regulatory pathway leading to lens formation.
Work is in progress to determine the role of Six3 during retina and later aspects of brain formation.