title: Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis.
abstract: 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.
authors.affiliation: Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7. fberry@ualberta.ca
authors.forename: Fred B
authors.initials: FB
authors.lastname: Berry
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Lines
authors.forename: J Martin
authors.initials: JM
authors.lastname: Oas
authors.forename: Tim
authors.initials: T
authors.lastname: Footz
authors.forename: D Alan
authors.initials: DA
authors.lastname: Underhill
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gage
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walter
mesh_terms: D000818:Animals; D000869:Anterior Eye Segment / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000097577:Homeobox Protein PITX2
chemical_list: D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C112743:FOXC1 protein, human