Journal Article

Functional interactions between FOXC1 and PITX2 underlie the sensitivity to <i>FOXC1</i> gene dose in Axenfeld–Rieger syndrome and anterior segment dysgenesis

Fred B. Berry, Matthew A. Lines, J. Martin Oas, Tim Footz, D. Alan Underhill, Philip J. Gage and Michael A. Walter

in Human Molecular Genetics

Volume 15, issue 6, pages 905-919
Published in print March 2006 | ISSN: 0964-6906
Published online January 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl008
Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld–Rieger syndrome and anterior segment dysgenesis

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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.

Journal Article.  7884 words.  Illustrated.

Subjects: Genetics and Genomics

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