title: YAP controls retinal stem cell DNA replication timing and genomic stability.
abstract: The adult frog retina retains a reservoir of active neural stem cells that contribute to continuous eye growth throughout life. We found that Yap, a downstream effector of the Hippo pathway, is specifically expressed in these stem cells. Yap knock-down leads to an accelerated S-phase and an abnormal progression of DNA replication, a phenotype likely mediated by upregulation of c-Myc. This is associated with an increased occurrence of DNA damage and eventually p53-p21 pathway-mediated cell death. Finally, we identified PKNOX1, a transcription factor involved in the maintenance of genomic stability, as a functional and physical interactant of YAP. Altogether, we propose that YAP is required in adult retinal stem cells to regulate the temporal firing of replication origins and quality control of replicated DNA. Our data reinforce the view that specific mechanisms dedicated to S-phase control are at work in stem cells to protect them from genomic instability.
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Cabochette
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Guillermo
authors.identifier: http://orcid.org/0000-0002-2426-2844
authors.initials: G
authors.lastname: Vega-Lopez
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Bitard
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Institute of Developmental Biochemistry, University of Goettingen, Goettingen, Germany.
authors.forename: Karine
authors.initials: K
authors.lastname: Parain
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Chemouny
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Masson
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Borday
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Institute of Developmental Biochemistry, University of Goettingen, Goettingen, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Hedderich
authors.affiliation: Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Institute of Developmental Biochemistry, University of Goettingen, Goettingen, Germany.
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Henningfeld
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Locker
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Bronchain
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Université Paris Sud, Orsay, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Perron
mesh_terms: D000818:Animals; D002455:Cell Division; D042522:DNA Replication Timing; D042822:Genomic Instability; D012160:Retina / Q000166:cytology*; D013234:Stem Cells / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D015534:Trans-Activators; D029867:Xenopus Proteins; C561677:YAP protein, Xenopus; D000091102:YAP-Signaling Proteins
keywords: Hippo/Yap pathway; cell proliferation; ciliary marginal zone; developmental biology; neural stem cells; retina; stem cells; xenopus