title: Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate.
abstract: As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors--atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)--occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York Eye Institute.
authors.forename: Fuguo
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York Eye Institute, Neuroscience Graduate Program, and.
authors.forename: Tadeusz J
authors.initials: TJ
authors.lastname: Kaczynski
authors.affiliation: Neuroscience Graduate Program, and Department of Physiology and Biophysics, University at Buffalo, Buffalo, NY 14203; and.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Sethuramanujam
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York Eye Institute.
authors.forename: Renzhong
authors.initials: R
authors.lastname: Li
authors.affiliation: Neuroscience Graduate Program, and Department of Physiology and Biophysics, University at Buffalo, Buffalo, NY 14203; and.
authors.forename: Varsha
authors.initials: V
authors.lastname: Jain
authors.affiliation: State University of New York Eye Institute, Neuroscience Graduate Program, and Department of Physiology and Biophysics, University at Buffalo, Buffalo, NY 14203; and.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Slaughter
authors.affiliation: Department of Ophthalmology/Ross Eye Institute, Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York Eye Institute, Neuroscience Graduate Program, and 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: D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D002490:Central Nervous System / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism*; D017403:In Situ Hybridization; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000196:embryology / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D050820:Transcription Factor Brn-3B / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors; C117638:Atoh7 protein, mouse; C085559:Pou4f2 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1
keywords: cell fate specification; gene regulation; neural development; retinal development; transcription factors