title: Lhx2 Is an Essential Factor for Retinal Gliogenesis and Notch Signaling.
abstract: Müller glia (MG) are the only glial cell type produced by the neuroepithelial progenitor cells that generate the vertebrate retina. MG are required to maintain retinal homeostasis and support the survival of retinal neurons. Furthermore, in certain vertebrate classes, MG function as adult stem cells, mediating retinal regeneration in response to injury. However, the mechanisms that regulate MG development are poorly understood because there is considerable overlap in gene expression between retinal progenitor cells and differentiated MG. We show that the LIM homeodomain transcription factor Lhx2 is required for the development of MG in the mouse retina. Temporally controlled knock-out studies reveal a requirement for Lhx2 during all stages of MG development, ranging from the proliferation of gliocompetent retinal progenitors, activation of Müller-specific gene expression, and terminal differentiation of MG morphological features. We show that Lhx2 regulates gliogenesis in part by regulating directly the expression of Notch pathway genes including Notch1, Dll1, and Dll3 and gliogenic transcription factors such as Hes1, Hes5, Sox8, and Rax. Conditional knock-out of Lhx2 resulted in a rapid downregulation of Notch pathway genes and loss of Notch signaling. We further demonstrate that Müller gliogenesis induced by misexpression of the potently gliogenic Notch pathway transcriptional effector Hes5 requires Lhx2 expression. These results indicate that Lhx2 not only directly regulates expression of Notch signaling pathway components, but also acts together with the gliogenic Notch pathway to drive MG specification and differentiation.
authors.affiliation: Solomon H. Snyder Department of Neuroscience.
authors.forename: Jimmy
authors.initials: J
authors.lastname: de Melo
authors.affiliation: Solomon H. Snyder Department of Neuroscience.
authors.forename: Cristina
authors.identifier: http://orcid.org/0000-0003-4922-1245
authors.initials: C
authors.lastname: Zibetti
authors.affiliation: Solomon H. Snyder Department of Neuroscience.
authors.forename: Brian S
authors.identifier: http://orcid.org/0000-0002-3473-6636
authors.initials: BS
authors.lastname: Clark
authors.affiliation: Department of Ophthalmology.
authors.forename: Woochang
authors.identifier: http://orcid.org/0000-0003-0489-3304
authors.initials: W
authors.lastname: Hwang
authors.affiliation: Department of Psychiatry, Universidad de Antioquia, Medellin, Columbia 050010.
authors.forename: Ana L
authors.identifier: http://orcid.org/0000-0002-1511-3644
authors.initials: AL
authors.lastname: Miranda-Angulo
authors.affiliation: Department of Ophthalmology.
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Department of Ophthalmology, Department of Neurology, High-Throughput Biology Center, and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and sblack@jhmi.edu.
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D060850:LIM-Homeodomain Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000096:biosynthesis*; D012160:Retina; D055351:Retinal Neurons / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D060850:LIM-Homeodomain Proteins; C489784:Lhx2 protein, mouse; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D014157:Transcription Factors
keywords: Lhx2; Müller glia; Notch; differentiation; retina