Tags

Type your tag names separated by a space and hit enter

Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis.
Hum Mol Genet. 2006 Mar 15; 15(6):905-19.HM

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+Show Affiliations

Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7. fberry@ualberta.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16449236

Citation

Berry, Fred B., et al. "Functional Interactions Between FOXC1 and PITX2 Underlie the Sensitivity to FOXC1 Gene Dose in Axenfeld-Rieger Syndrome and Anterior Segment Dysgenesis." Human Molecular Genetics, vol. 15, no. 6, 2006, pp. 905-19.
Berry FB, Lines MA, Oas JM, et al. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet. 2006;15(6):905-19.
Berry, F. B., Lines, M. A., Oas, J. M., Footz, T., Underhill, D. A., Gage, P. J., & Walter, M. A. (2006). Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Human Molecular Genetics, 15(6), 905-19.
Berry FB, et al. Functional Interactions Between FOXC1 and PITX2 Underlie the Sensitivity to FOXC1 Gene Dose in Axenfeld-Rieger Syndrome and Anterior Segment Dysgenesis. Hum Mol Genet. 2006 Mar 15;15(6):905-19. PubMed PMID: 16449236.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. AU - Berry,Fred B, AU - Lines,Matthew A, AU - Oas,J Martin, AU - Footz,Tim, AU - Underhill,D Alan, AU - Gage,Philip J, AU - Walter,Michael A, Y1 - 2006/01/31/ PY - 2006/2/2/pubmed PY - 2007/11/6/medline PY - 2006/2/2/entrez SP - 905 EP - 19 JF - Human molecular genetics JO - Hum Mol Genet VL - 15 IS - 6 N2 - 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. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/16449236/Functional_interactions_between_FOXC1_and_PITX2_underlie_the_sensitivity_to_FOXC1_gene_dose_in_Axenfeld_Rieger_syndrome_and_anterior_segment_dysgenesis_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddl008 DB - PRIME DP - Unbound Medicine ER -