title: A complex regulatory network of transcription factors critical for ocular development and disease.
abstract: The PITX2 'homeobox' and FOXC1 and FOXC2 'forkhead box' transcription factors are critical for eye development and cause human ocular diseases when mutated. We have identified biochemical and genetic links between these transcription factors and a transcriptional regulator protein PRKC apoptosis Wilms' tumor 1 regulator (PAWR) that we propose to functionally connect all these proteins in a common pathway critically involved in eye development. We discovered all binary physical interactions between FOXC1, PITX2, FOXC2 and PAWR. Importantly, PAWR modulates the abilities of PITX2, FOXC1 and FOXC2 to activate their genetic targets. Together with either FOXC1 or FOXC2, PAWR increases PITX2 activity. PAWR reduces PITX2 activity in the absence of FOXC1 or FOXC2. At the same time, PAWR also exerts different regulatory effects on different FOXC target sites. Furthermore, morpholino knockdown of pitx2, foxc1 and pawr in zebrafish indicate that PAWR, FOXC1 and PITX2 genetically interact, and are in the same developmental pathway. These data for the first time tie PITX2, FOXC1, FOXC2 and PAWR into a common regulatory pathway. We have therefore identified a functional link between three transcription factors, modulated by PAWR, which we propose underlies the similar ocular phenotypes and glaucoma pathology caused by mutations of these genes.
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada T6G 2H7. moulinat@ulaberta.ca
authors.forename: Moulinath
authors.initials: M
authors.lastname: Acharya
authors.forename: Lijia
authors.initials: L
authors.lastname: Huang
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Fleisch
authors.forename: W Ted
authors.initials: WT
authors.lastname: Allison
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walter
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005123:Eye / Q000196:embryology* / Q000254:growth & development*; D005128:Eye Diseases / Q000235:genetics*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000254:growth & development*; D000097577:Homeobox Protein PITX2
chemical_list: D051017:Apoptosis Regulatory Proteins; D005346:Fibroblast Growth Factors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C117476:FGF19 protein, human; C112743:FOXC1 protein, human; C085126:FOXO1 protein, human; C082078:mesenchyme fork head 1 protein; C101296:prostate apoptosis response-4 protein