Open AccessNotch Signaling Activates Stem Cell Properties of Müller Glia through Transcriptional Regulation and Skp2-mediated Degradation of p27Kip1
Author(s) -
Carolina Beltrame Del Debbio,
Qulsum Mir,
Sowmya Parameswaran,
Saumi Mathews,
Xiaohuan Xia,
Zheng Li,
Andrew J. Neville,
Iqbal Ahmad
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0152025
Subject(s) - notch signaling pathway , microbiology and biotechnology , biology , stem cell , hes3 signaling axis , signal transduction , cellular differentiation , skp2 , muller glia , progenitor cell , cell signaling , regeneration (biology) , notch proteins , cell cycle , cell , ubiquitin , ubiquitin ligase , biochemistry , gene
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), p27 Kip1 , which is highly expressed in quiescent MG. Notch signaling facilitates the activation of MG by inhibiting p27 Kip1 expression. This is likely achieved through the Notch- p27 Kip1 and Notch-Skp2-p27 Kip1 axes, the former inhibiting the expression of p27 Kip1 transcripts and the latter levels of p27 Kip1 proteins by Skp2-mediated proteasomal degradation. Thus, Notch signaling may facilitate re-entry of MG into the cell cycle by inhibiting p27 Kip1 expression both transcriptionally and post-translationally.