title: Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development.
abstract: Previously, we have shown that Onecut1 (Oc1) and Onecut2 (Oc2) are expressed in retinal progenitor cells, developing retinal ganglion cells (RGCs), and horizontal cells (HCs). However, in Oc1-null mice, we only observed an 80% reduction in HCs, but no defects in other cell types. We postulated that the lack of defects in other cell types in Oc1-null retinas was a result of redundancy with Oc2. To test this theory, we have generated Oc2-null mice and now show that their retinas also only have defects in HCs, with a 50% reduction in their numbers. However, when both Oc1 and Oc2 are knocked out, the retinas exhibit more profound defects in the development of all early retinal cell types, including completely failed genesis of HCs, compromised generation of cones, reduced production (by 30%) of RGCs, and absence of starburst amacrine cells. Cone subtype diversification and RGC subtype composition also were affected in the double-null retina. Using RNA-Seq expression profiling, we have identified downstream genes of Oc1 and Oc2, which not only confirms the redundancy between the two factors and renders a molecular explanation for the defects in the double-null retinas, but also shows that the onecut factors suppress the production of the late cell type, rods, indicating that the two factors contribute to the competence of retinal progenitor cells for the early retinal cell fates. Our results provide insight into how onecut factors regulate the creation of cellular diversity in the retina and, by extension, in the central nervous system in general.
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Department of Biochemistry, Developmental Genomics Group, State University of New York Eye Institute, Buffalo, NY 14203;
authors.forename: Darshan
authors.initials: D
authors.lastname: Sapkota
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Developmental Genomics Group, State University of New York Eye Institute, Buffalo, NY 14203;
authors.forename: Hemabindu
authors.initials: H
authors.lastname: Chintala
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Developmental Genomics Group, State University of New York Eye Institute, Buffalo, NY 14203;
authors.forename: Fuguo
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, State University of New York Eye Institute, Buffalo, NY 14203; Research Service, Veterans Administration Western New York Healthcare System, Buffalo, NY 14215; and.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fliesler
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, State University of New York Eye Institute, Buffalo, NY 14203; Department of Biostatistics, Department of Medicine, and Center of Computational Research, New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203;
authors.forename: Zihua
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Department of Biochemistry, Developmental Genomics Group, State University of New York Eye Institute, Buffalo, NY 14203; Cancer Center Support Grant Cancer Genetics Program, Roswell Park Cancer Institute, Buffalo, NY 14263 xmu@buffalo.edu.
authors.forename: Xiuqian
authors.initials: X
authors.lastname: Mu
mesh_terms: D025042:Amacrine Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051559:Hepatocyte Nuclear Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D012160:Retina / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D051248:Retinal Horizontal Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; C487964:ONECUT2 protein, mouse; C496606:Onecut1 protein, mouse; D014157:Transcription Factors
keywords: cell fate determination; gene regulation; neural development; retinal development; transcription factors