title: The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis.
abstract: The Lim domain-binding proteins are key co-factor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation. Using conditional mutagenesis and comparative phenotypic analysis, we analyze the function of Ldb1 and Ldb2 in mouse retinal development, and demonstrate overlapping and specific functions of both proteins. Ldb1 interacts with Lhx2 in the embryonic retina and both Ldb1 and Ldb2 play a key role in maintaining the pool of retinal progenitor cells. This is accomplished by controlling the expression of the Vsx2 and Rax, and components of the Notch and Hedgehog signaling pathways. Furthermore, the Ldb1/Ldb2-mediated complex is essential for generation of early-born photoreceptors through the regulation of Rax and Crx. Finally, we demonstrate functional redundancy between Ldb1 and Ldb2. Ldb1 can fully compensate the loss of Ldb2 during all phases of retinal development, whereas Ldb2 alone is sufficient to sustain activity of Lhx2 in both early- and late-stage RPCs and in Müller glia. By contrast, loss of Ldb1 disrupts activity of the LIM domain factors in neuronal precursors. An intricate regulatory network exists that is mediated by Ldb1 and Ldb2, and promotes RPC proliferation and multipotency; it also controls specification of mammalian retina cells.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Gueta
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ahuvit
authors.initials: A
authors.lastname: David
authors.affiliation: Mammalian Genes and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tsadok
authors.initials: T
authors.lastname: Cohen
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Menuchin-Lasowski
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Nobel
authors.affiliation: Mammalian Genes and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ginat
authors.initials: G
authors.lastname: Narkis
authors.affiliation: Program on Genomics of Differentiation, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: LiQi
authors.initials: L
authors.lastname: Li
authors.affiliation: Program on Genomics of Differentiation, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Love
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: de Melo
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.affiliation: Mammalian Genes and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel ruthash@post.tau.ac.il.
authors.forename: Ruth
authors.identifier: 0000-0002-5364-6898
authors.initials: R
authors.lastname: Ashery-Padan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000502:physiology; D060588:LIM Domain Proteins / Q000502:physiology*; D008322:Mammals / Q000196:embryology / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D038081:Organogenesis / Q000235:genetics*; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C102084:Ldb1 protein, mouse; C106649:Ldb2 protein, mouse; D014157:Transcription Factors
keywords: Isl1; Ldb1; Lhx2; Retinogenesis