Notch signaling activates stem cell properties of Müller glia through transcriptional regulation and Skp2-mediated degradation of p27Kip1

Carolina Beltrame Del Debbio, Qulsum Mir, Sowmya Parameswaran, Saumi Mathews, Xiaohuan Xia, Li Zheng, Andrew J. Neville, Iqbal Ahmad

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0152025
JournalPloS one
Volume11
Issue number3
DOIs
StatePublished - Mar 24 2016

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Stem cells
Neuroglia
stem cells
Stem Cells
Degradation
degradation
cyclin-dependent kinase
neuroglia
cell cycle
vertebrates
therapeutics
Chemical activation
proteins
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases
Reentry
Vertebrates
Regeneration
Cell Cycle
Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Notch signaling activates stem cell properties of Müller glia through transcriptional regulation and Skp2-mediated degradation of p27Kip1. / Del Debbio, Carolina Beltrame; Mir, Qulsum; Parameswaran, Sowmya; Mathews, Saumi; Xia, Xiaohuan; Zheng, Li; Neville, Andrew J.; Ahmad, Iqbal.

In: PloS one, Vol. 11, No. 3, e0152025, 24.03.2016.

Research output: Contribution to journalArticle

Del Debbio, Carolina Beltrame ; Mir, Qulsum ; Parameswaran, Sowmya ; Mathews, Saumi ; Xia, Xiaohuan ; Zheng, Li ; Neville, Andrew J. ; Ahmad, Iqbal. / Notch signaling activates stem cell properties of Müller glia through transcriptional regulation and Skp2-mediated degradation of p27Kip1. In: PloS one. 2016 ; Vol. 11, No. 3.
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abstract = "M{\"u}ller 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.",
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