title: Activin/Nodal Signaling Supports Retinal Progenitor Specification in a Narrow Time Window during Pluripotent Stem Cell Neuralization.
abstract: Retinal progenitors are initially found in the anterior neural plate region known as the eye field, whereas neighboring areas undertake telencephalic or hypothalamic development. Eye field cells become specified by switching on a network of eye field transcription factors, but the extracellular cues activating this network remain unclear. In this study, we used chemically defined media to induce in vitro differentiation of mouse embryonic stem cells (ESCs) toward eye field fates. Inhibition of Wnt/β-catenin signaling was sufficient to drive ESCs to telencephalic, but not retinal, fates. Instead, retinal progenitors could be generated from competent differentiating mouse ESCs by activation of Activin/Nodal signaling within a narrow temporal window corresponding to the emergence of primitive anterior neural progenitors. Activin also promoted eye field gene expression in differentiating human ESCs. Our results reveal insights into the mechanisms of eye field specification and open new avenues toward the generation of retinal progenitors for translational medicine.
authors.affiliation: Laboratorio di Biologia, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56124 Pisa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Bertacchi
authors.affiliation: Department of Chemistry, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lupo
authors.affiliation: Laboratorio di Biologia, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56124 Pisa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pandolfini
authors.affiliation: Centre for Integrative Biology, University of Trento, Via delle Regole 101, 38123 Mattarello (Trento), Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Casarosa
authors.affiliation: Genomics Facility, European Brain Research Institute "Rita Levi-Montalcini," Via del Fosso di Fiorano 64, 00143 Rome, Italy; Istituto di Farmacologia Traslazionale, CNR, Via del Fosso del Cavaliere 100, 00133 Rome, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: D'Onofrio
authors.affiliation: Department of Surgery and The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, West Forvie Building, Robinson Way, Cambridge CB2 0SZ, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Pedersen
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
authors.forename: William A
authors.initials: WA
authors.lastname: Harris
authors.affiliation: Laboratorio di Biologia, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56124 Pisa, Italy; Institute of Biomedical Technologies (ITB), National Research Council (CNR) of Pisa, Via Moruzzi 1, 56124 Pisa, Italy. Electronic address: federico.cremisi@sns.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Cremisi
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055457:Nodal Protein / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction; D060449:Wnt Signaling Pathway
chemical_list: D055457:Nodal Protein; C526008:Nodal protein, mouse; D028341:Activins