Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6.
The transcription factors Pax2 and Pax6 are co-expressed in the entire optic vesicle (OV) prior and concomitant with the establishment of distinct neuroretinal, retinal, pigmented-epithelial and optic-stalk progenitor domains, suggesting redundant functions during retinal determination. Pax2; Pax6 compound mutants display a dose-dependent reduction in the expression of the melanocyte determinant Mitf, accompanied by transdifferentiation of retinal pigmented epithelium (RPE) into neuroretina (NR) in Pax2(-/-); Pax6(+/-) embryos, which strongly resembles the phenotype of Mitf-null mutants. In Pax2(-/-); Pax6(-/-) OVs Mitf fails to be expressed and NR markers occupy the area that usually represents the Mitf(+) RPE domain. Furthermore, both, Pax2 and Pax6 bind to and activate a MITF RPE-promoter element in vitro, whereas prolonged expression of Pax6 in the Pax2-positive optic stalk leads to ectopic Mitf expression and RPE differentiation in vivo. Together, these results demonstrate that the redundant activities of Pax2 and Pax6 direct the determination of RPE, potentially by directly controlling the expression of RPE determinants.
Bäumer
Nicole
N
Department of Molecular Cell Biology, Max-Planck-Institute of Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany.
Marquardt
Till
T
Stoykova
Anastassia
A
Spieler
Derek
D
Treichel
Dieter
D
Ashery-Padan
Ruth
R
Gruss
Peter
P
D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor; D051762:PAX2 Transcription Factor; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000196:embryology* / Q000254:growth & development / Q000502:physiology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors