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Felix R. Vazquez-Chona, Alyssa Lolofie, Dennis M. Defoe, Edward M. Levine; Genetic Dissection Of p27-mediated Reactive Müller Gliosis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2674.
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In an effort to identify key regulators of glial reactivity, we previously showed that global conditional inactivation of the cyclin-dependent kinase (CDK) inhibitor p27Kip1 induces Müller glia to proliferate, migrate, and upregulate intermediate filaments. Here, we address whether p27 inactivation acts cell autonomously to induce Müller glial reactivity, and whether p27 modulates Müller glial reactivity through its CDK/cyclin (CK) domain or through its phosphorylation state at serine-10 (S10).
We conditionally targeted the p27 coding region in adult mice harboring the p27LoxP (p27L+) mutation and expressing a tamoxifen-inducible Cre-recombinase under the control of a glial promoter, GLAST-CreERT2. To determine which p27-domain modulates reactive gliosis we induced light damage in mice harboring either the CK- mutation or S10A knock-in mutation.
Glial-specific p27 inactivation resulted in proliferative Müller glial reactivity. p27+/ck- retinas displayed enhanced levels of reactivity relative to the wild-type and p27S10A/S10A retinas after light-induced retinal degeneration.
Preliminary data suggest that p27 regulates Müller glial reactivity through its CK domain. These findings also suggest that p27 is a key modulator of glial plasticity and its pathway represents a prime target to facilitate glial based regeneration and to modulate glial scar formation.
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