title: Vax2 regulates retinoic acid distribution and cone opsin expression in the vertebrate eye.
abstract: Vax2 is an eye-specific homeobox gene, the inactivation of which in mouse leads to alterations in the establishment of a proper dorsoventral eye axis during embryonic development. To dissect the molecular pathways in which Vax2 is involved, we performed a transcriptome analysis of Vax2(-/-) mice throughout the main stages of eye development. We found that some of the enzymes involved in retinoic acid (RA) metabolism in the eye show significant variations of their expression levels in mutant mice. In particular, we detected an expansion of the expression domains of the RA-catabolizing enzymes Cyp26a1 and Cyp26c1, and a downregulation of the RA-synthesizing enzyme Raldh3. These changes determine a significant expansion of the RA-free zone towards the ventral part of the eye. At postnatal stages of eye development, Vax2 inactivation led to alterations of the regional expression of the cone photoreceptor genes Opn1sw (S-Opsin) and Opn1mw (M-Opsin), which were significantly rescued after RA administration. We confirmed the above described alterations of gene expression in the Oryzias latipes (medaka fish) model system using both Vax2 gain- and loss-of-function assays. Finally, a detailed morphological and functional analysis of the adult retina in mutant mice revealed that Vax2 is necessary for intraretinal pathfinding of retinal ganglion cells in mammals. These data demonstrate for the first time that Vax2 is both necessary and sufficient for the control of intraretinal RA metabolism, which in turn contributes to the appropriate expression of cone opsins in the vertebrate eye.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Alfano
authors.forename: Ivan
authors.initials: I
authors.lastname: Conte
authors.forename: Tiziana
authors.initials: T
authors.lastname: Caramico
authors.forename: Raffaella
authors.initials: R
authors.lastname: Avellino
authors.forename: Benedetta
authors.initials: B
authors.lastname: Arnò
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pizzo
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Beck
authors.forename: Gesine
authors.initials: G
authors.lastname: Huber
authors.forename: Pascal
authors.initials: P
authors.lastname: Dollé
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Sandro
authors.initials: S
authors.lastname: Banfi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072500:Cytochrome P450 Family 26; D005123:Eye / Q000254:growth & development* / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055355:Opsins / Q000235:genetics / Q000378:metabolism*; D009990:Oryzias / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D011247:Pregnancy; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D017299:Rod Opsins / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D055355:Opsins; D017299:Rod Opsins; C120595:Vax2 protein, mouse; C095853:short-wavelength opsin; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607080:Cyp26a1 protein, mouse; C495026:Cyp26c1 protein, mouse; D000072500:Cytochrome P450 Family 26; D000072516:Retinoic Acid 4-Hydroxylase