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Edward Levine, Dennis M Defoe, Felix Vazquez-Chona; Tumor suppressor p27KIP1 modulates cell-cycle entry and limited neurogenic potential in radial Müller glia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4186.
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© ARVO (1962-2015); The Authors (2016-present)
The proliferative response of Müller glia is a target of regeneration strategies. However, uncontrolled glial activation also contributes to gliosis and tissue remodeling. In an effort to identify key regulators of proliferative reactive gliosis, we address whether p27KIP1 is a negative of regulator Müller glial cell-cycle entry and neurogenic potential as well as of non-proliferative responses such as migration and GFAP upregulation.
We conditionally targeted the p27 coding region in adult mice harboring the p27LoxP mutation and expressing a tamoxifen-inducible Cre-recombinase under the control of glial promoter GLAST. We also induced transgenic p27 expression in retinal degeneration models using the ROSA26 promoter and Cre-Lox technology. To determine which p27-domain modulates reactive gliosis we induced light damage in mice harboring mutations in either its CDK/cyclin (CK) domain or through its phosphorylation state at serine-10 (S10).
Glial-specific p27 inactivation induced enhanced expression cell-cycle entry markers (PCNA and Ki67) with limited expression of mitotic marker phospho-histone H3. p27-deficient Müller glia also displayed re-expression of late progenitor markers such as MCM6 and OTX2 but resulted in additional Müller glia or underwent cell death. Transgenic p27 expression decreased Müller glial proliferation and outer limiting membrane (OLM) breakdowns but was insufficient to block GFAP expression. Mutations in p27 CDK/cyclin domain enhanced nuclear translocation and OLM breakdowns after light-induced retinal degeneration.
Our genetic experiments suggest that p27 activity is most closely associated with migratory behavior and cell-cycle entry, whereas GFAP upregulation appears to be a secondary event. Thus, p27 is a prime target to facilitate the first step in regeneration strategies: Müller glial proliferation. Increasing p27 activity may also limit scar formation and OLM breakdowns of during trauma or post-operative eye surgery.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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