title: Pax6 dosage requirements in iris and ciliary body differentiation.
abstract: Pax6 is a highly conserved transcription factor that controls the morphogenesis of various organs. Changes in Pax6 dosage have been shown to affect the formation of multiple tissues. PAX6 haploinsufficiency leads to aniridia, a pan-ocular disease primarily characterized by iris hypoplasia. Herein, we employ a modular system that includes null and overexpressed conditional alleles of Pax6. The use of the Tyrp2-Cre line, active in iris and ciliary body (CB) primordium, enabled us to investigate the effect of varying dosages of Pax6 on the development of these ocular sub-organs. Our findings show that a lack of Pax6 in these regions leads to dysgenesis of the iris and CB, while heterozygosity impedes growth of the iris and maturation of the iris sphincter. Overexpression of the canonical, but not the alternative splice variant of Pax6 results in severe structural aberrations of the CB and hyperplasia of the iris sphincter. A splice variant-specific rescue experiment revealed that both splice variants are able to correct iris hypoplasia, while only the canonical form rescues the sphincter. Overall, these findings demonstrate the dosage-sensitive roles of Pax6 in the formation of both the CB and the iris.
authors: Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel.
authors: Noa
authors: N
authors: Davis
authors: Chen
authors: C
authors: Yoffe
authors: Shaul
authors: S
authors: Raviv
authors: Ran
authors: R
authors: Antes
authors: Joachim
authors: J
authors: Berger
authors: Silvia
authors: S
authors: Holzmann
authors: Anastassia
authors: A
authors: Stoykova
authors: Paul A
authors: PA
authors: Overbeek
authors: Ernst R
authors: ER
authors: Tamm
authors: Ruth
authors: R
authors: Ashery-Padan
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation; D002924:Ciliary Body / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D018628:Gene Dosage; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D007498:Iris / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins