Pax6 controls the proliferation rate of neuroepithelial progenitors from the mouse optic vesicle.
In vertebrates, a limited number of homeobox-containing transcription factors are expressed in the optic vesicle primordium and are required and sufficient for eye formation. At present, little is known about the distinct functions of these factors in optic vesicle growth and on the nature of the main neuroepithelial (NE) progenitor population present in this organ. We have characterized a multipotent cell population present in the mouse optic vesicle that shows extensive proliferation potential and which expresses NE progenitor and retinal markers in vitro. In Pax6 mutant embryos, which form an optic vesicle, we found that the number of resident NE progenitors was greater than normal. In vitro, Pax6-null NE progenitors overproliferate and display reduced p16(Ink4a), p19(Arf), p27(kip1), p57(kip2), and p21(cip1) expression. Pax6 overexpression repressed cellular proliferation and secondary colonies formation, supporting the hypothesis that Pax6 acts cell-autonomously on NE progenitors cell cycle. Notably, these in vitro data correlated with aberrant numbers of mitosis observed in the optic vesicle of early stage Pax6 mutants, with Pax6 association with the chromatin upstream of p27(kip1) promoter region, and with reduced expression levels of p27(kip1), p57(kip2), and p21(cip1) in the primitive forebrain of Pax6 mutants. Taken together, our results suggest that, prior to retinal progenitor cell identity and neurogenesis, Pax6 is required to regulate the proliferation rate of NE progenitors present in the mouse optic vesicle.
Duparc
Robert-Hugues
RH
Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, 5415 Boul. l'Assomption, Montreal, Canada H1T 2M4.
Abdouh
Mohamed
M
David
Jocelyn
J
Lépine
Mireille
M
Tétreault
Nicolas
N
Bernier
Gilbert
G
D000818:Animals; D015415:Biomarkers; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism; D005123:Eye / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D046569:Neuroepithelial Cells / Q000166:cytology* / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
D015415:Biomarkers; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D018844:Cyclin-Dependent Kinases