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Berry, F.B. et al.

Berry, Lines, Oas, Footz, Underhill, Gage, Walter,

Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis.

Axenfeld-Rieger ocular dysgenesis is associated with mutations of the human PITX2 and FOXC1 genes, which encode transcription factors of the homeodomain and forkhead types, respectively. We have identified a functional link between FOXC1 and PITX2 which we propose underpins the similar Axenfeld-Rieger phenotype caused by mutations of these genes. FOXC1 and PITX2A physically interact, and this interaction requires crucial functional domains on both proteins: the C-terminal activation domain of FOXC1 and the homeodomain of PITX2. Immunofluorescence further shows PITX2A and FOXC1 to be colocalized within a common nuclear subcompartment. Furthermore, PITX2A can function as a negative regulator of FOXC1 transactivity. This work ties both proteins into a common pathway and offers an explanation of why increased FOXC1 gene dosage produces a phenotype resembling that of PITX2 deletions and mutations. Ocular phenotypes arise despite the deregulated expression of FOXC1- target genes through mutations in FOXC1 or PITX2. Ultimately, PITX2 loss of function mutations have a compound effect: the reduced expression of PITX2- target genes coupled with the extensive activation of FOXC1-regulated targets. Our findings indicate that the functional interaction between FOXC1 and PITX2A underlies the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and related anterior segment dysgeneses.[1]

References

Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Berry, F.B., Lines, M.A., Oas, J.M., Footz, T., Underhill, D.A., Gage, P.J., Walter, M.A. Hum. Mol. Genet. (2006) [Pubmed]

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