title: A Notch-Gli2 axis sustains Hedgehog responsiveness of neural progenitors and Müller glia.
abstract: Neurogenesis is regulated by the dynamic and coordinated activity of several extracellular signalling pathways, but the basis for crosstalk between these pathways remains poorly understood. Here we investigated regulatory interactions between two pathways that are each required for neural progenitor cell maintenance in the postnatal retina; Hedgehog (Hh) and Notch signalling. Both pathways are activated in progenitor cells in the postnatal retina based on the co-expression of fluorescent pathway reporter transgenes at the single cell level. Disrupting Notch signalling, genetically or pharmacologically, induces a rapid downregulation of all three Gli proteins and inhibits Hh-induced proliferation. Ectopic Notch activation, while not sufficient to promote Hh signalling or proliferation, increases Gli2 protein. We show that Notch regulation of Gli2 in Müller glia renders these cells competent to proliferate in response to Hh. These data suggest that Notch signalling converges on Gli2 to prime postnatal retinal progenitor cells and Müller glia to proliferate in response to Hh.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Randy
authors.initials: R
authors.lastname: Ringuette
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Michael
authors.initials: M
authors.lastname: Atkins
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Lagali
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Bassett
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Charles
authors.initials: C
authors.lastname: Campbell
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mazerolle
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mears
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6; Department of Biochemistry, Microbiology and Immunology, Department of Ophthalmology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: David J
authors.initials: DJ
authors.lastname: Picketts
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6; Department of Biochemistry, Microbiology and Immunology, Department of Ophthalmology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5; Vision Research Division, Krembil Research Institute, University Health Network and Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: vwallace@uhnresearch.ca.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Wallace
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D063928:Ependymoglial Cells / Q000166:cytology*; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000196:embryology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C486455:Maml1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
keywords: Competency; Gli transcription factors; Gli2; Hedgehog; Müller glia; Neural progenitor; Notch; Proliferation; Retinal histogenesis