title: Notch Signaling Activates Stem Cell Properties of Müller Glia through Transcriptional Regulation and Skp2-mediated Degradation of p27Kip1.
abstract: Müller glia (MG), the sole glial cells generated by retinal progenitors, have emerged as a viable cellular target for therapeutic regeneration in degenerative blinding diseases, as they possess dormant stem cell properties. However, the mammalian MG does not display the neurogenic potential of their lower vertebrate counterparts, precluding their practical clinical use. The answer to this barrier may be found in two interlinked processes underlying the neurogenic potential, i.e., the activation of the dormant stem cell properties of MG and their differentiation along the neuronal lineage. Here, we have focused on the former and examined Notch signaling-mediated activation of MG. We demonstrate that one of the targets of Notch signaling is the cyclin-dependent kinase inhibitor (CKI), p27Kip1, which is highly expressed in quiescent MG. Notch signaling facilitates the activation of MG by inhibiting p27Kip1 expression. This is likely achieved through the Notch- p27Kip1 and Notch-Skp2-p27Kip1 axes, the former inhibiting the expression of p27Kip1 transcripts and the latter levels of p27Kip1 proteins by Skp2-mediated proteasomal degradation. Thus, Notch signaling may facilitate re-entry of MG into the cell cycle by inhibiting p27Kip1 expression both transcriptionally and post-translationally.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Carolina Beltrame
authors.initials: CB
authors.lastname: Del Debbio
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Qulsum
authors.initials: Q
authors.lastname: Mir
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Parameswaran
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Saumi
authors.initials: S
authors.lastname: Mathews
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Neville
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000196:embryology; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051880:Receptors, Notch; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27