title: Conditional deletion of AP-2β in mouse cranial neural crest results in anterior segment dysgenesis and early-onset glaucoma.
abstract: Anterior segment dysgenesis (ASD) encompasses a group of developmental disorders in which a closed angle phenotype in the anterior chamber of the eye can occur and 50% of patients develop glaucoma. Many ASDs are thought to involve an inappropriate patterning and migration of the periocular mesenchyme (POM), which is derived from cranial neural crest cells (NCCs) and mesoderm. Although, the mechanism of this disruption is not well understood, a number of transcriptional regulatory molecules have previously been implicated in ASDs. Here, we investigate the function of the transcription factor AP-2β, encoded by Tfap2b, which is expressed in NCCs and their derivatives. Wnt1-Cre-mediated conditional deletion of Tfap2b in NCCs resulted in post-natal ocular defects typified by opacity. Histological data revealed that the conditional AP-2β NCC knockout (KO) mutants exhibited dysgenesis of multiple structures in the anterior segment of the eye including defects in the corneal endothelium, corneal stroma, ciliary body and disruption in the iridocorneal angle with adherence of the iris to the cornea. We further show that this phenotype leads to a significant increase in intraocular pressure and a subsequent loss of retinal ganglion cells and optic nerve degeneration, features indicative of glaucoma. Overall, our findings demonstrate that AP-2β is required in the POM for normal development of the anterior segment of the eye and that the AP-2β NCC KO mice might serve as a new and exciting model of ASD and glaucoma that is fully penetrant and with early post-natal onset.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Room 4N65, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Vanessa B
authors.initials: VB
authors.lastname: Martino
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Room 4N65, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sabljic
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Room 4N65, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Paula
authors.initials: P
authors.lastname: Deschamps
authors.affiliation: Department of Craniofacial Biology, University of Colorado Denver, Anschutz Medical Campus, Mailstop 8120, RC-1 South Building, 11th Floor, Room 111, 12801 East 17th Ave. P.O., Aurora, CO 80045, USA Department of Cell and Developmental Biology, University of Colorado Denver, Anschutz Medical Campus, Mailstop 8120, RC-1 South Building, 11th Floor, Room 111, 12801 East 17th Ave. P.O., Aurora, CO 80045, USA.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Green
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Room 4N65, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Monica
authors.initials: M
authors.lastname: Akula
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Room 4N65, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Erica
authors.initials: E
authors.lastname: Peacock
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Room 4N65, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ball
authors.affiliation: Department of Craniofacial Biology, University of Colorado Denver, Anschutz Medical Campus, Mailstop 8120, RC-1 South Building, 11th Floor, Room 111, 12801 East 17th Ave. P.O., Aurora, CO 80045, USA Department of Cell and Developmental Biology, University of Colorado Denver, Anschutz Medical Campus, Mailstop 8120, RC-1 South Building, 11th Floor, Room 111, 12801 East 17th Ave. P.O., Aurora, CO 80045, USA Trevor.Williams@ucdenver.edu westmayj@mcmaster.ca.
authors.forename: Trevor
authors.identifier: 0000-0001-9204-2731
authors.initials: T
authors.lastname: Williams
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Room 4N65, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5 Trevor.Williams@ucdenver.edu westmayj@mcmaster.ca.
authors.forename: Judith A
authors.identifier: 0000-0003-4293-9131
authors.initials: JA
authors.lastname: West-Mays
mesh_terms: D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities* / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D001369:Axons / Q000473:pathology; D002452:Cell Count; D003315:Cornea / Q000002:abnormalities / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D005124:Eye Abnormalities / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D017353:Gene Deletion; D005901:Glaucoma / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D007429:Intraocular Pressure; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009432:Neural Crest / Q000378:metabolism*; D009457:Neuroglia / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism; D012886:Skull / Q000473:pathology*; D050656:Transcription Factor AP-2 / Q000235:genetics*
chemical_list: C493669:Tfap2b protein, mouse; D050656:Transcription Factor AP-2
keywords: AP-2β; Anterior segment dysgenesis; Glaucoma