title: Vax1/2 genes counteract Mitf-induced respecification of the retinal pigment epithelium.
abstract: During vertebrate eye development, the transcription factor MITF acts to promote the development of the retinal pigment epithelium (RPE). In embryos with Mitf mutations, the future RPE hyperproliferates and is respecified as retinal tissue but only in a small portion of the dorsal RPE. Using a series of genetic crosses, we show that this spatial restriction of RPE respecification is brought about by persistent expression of the anti-retinogenic ventral homeodomain gene Vax2 in the dorso-proximal and both Vax1 and Vax2 in the ventral RPE. We further show that dorso-proximal RPE respecification in Vax2/Mitf double mutants and dorso-proximal and ventral RPE respecification in Vax1/2/Mitf triple mutants result from increased FGF/MAP kinase signaling. In none of the mutants, however, does the distal RPE show signs of hyperproliferation or respecification, likely due to local JAGGED1/NOTCH signaling. Expression studies and optic vesicle culture experiments also suggest a role for NOTCH signaling within the mutant dorsal RPE domains, where ectopic JAGGED1 expression may partially counteract the effects of FGF/ERK1/2 signaling on RPE respecification. The results indicate the presence of complex interplays between distinct transcription factors and signaling molecules during eye development and show how RPE phenotypes associated with mutations in one gene are modulated by expression changes in other genes.
authors.affiliation: Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. ouj@nei.nih.gov
authors.forename: Jingxing
authors.initials: J
authors.lastname: Ou
authors.forename: Kapil
authors.initials: K
authors.lastname: Bharti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nodari
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertuzzi
authors.forename: Heinz
authors.initials: H
authors.lastname: Arnheiter
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D004843:Epistasis, Genetic; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D009479:Neuropeptides; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C485177:Vax1 protein, mouse; C120595:Vax2 protein, mouse; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases
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