Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function

Abstract

BackgroundThe response of mammalian glial cells to chronic degeneration and trauma is hypothesized to be incompatible with support of neuronal function in the central nervous system (CNS) and retina. To test this hypothesis, we developed an inducible model of proliferative reactive gliosis in the absence of degenerative stimuli by genetically inactivating the cyclin-dependent kinase inhibitor p27Kip1 (p27 or Cdkn1b) in the adult mouse and determined the outcome on retinal structure and function.Resultsp27-deficient Müller glia reentered the cell cycle, underwent aberrant migration, and enhanced their expression of intermediate filament proteins, all of which are characteristics of Müller glia in a reactive state. Surprisingly, neuroglial interactions, retinal electrophysiology, and visual acuity were normal.ConclusionThe benign outcome of proliferative reactive Müller gliosis suggests that reactive glia display context-dependent, graded and dynamic phenotypes and that reactivity in itself is not necessarily detrimental to neuronal function.

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

“…Although murine Müller glia do not proliferate after most forms of retinal injury (1,13), previous studies have demonstrated that, in certain severe pathological conditions as well as after genetic deletion of P27 Kip1 , these cells may undergo proliferative reactive gliosis (14,15). We did not observe any change in Ki67 expression in Lhx2 ΔcKO retinas at either P26 or P55 (Fig.…”

Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish

“…In zebrafish Müller glia, p27 kip1 is down-regulated by 8 h after acute light lesion (Qin et al, 2009) and by 16 h of light exposure in a chronic lesion (Kassen et al, 2007). Similarly, mouse Müller glia down-regulate p27 kip1 and up-regulate GFAP after injury (Dyer and Cepko, 2000a), and in both the injured and uninjured mouse retina, p27 kip1 deficiency leads to reactive gliosis in Müller glia (Dyer and Cepko, 2000a; Vazquez-Chona et al, 2011). During mouse retinal development, p57 kip2 is expressed in the final cell cycle and in a subset of progenitors different from the p27 kip1 -positive cells (Dyer and Cepko, 2000b, 2001).…”

“…A recent study by Edward Levine, Robert Marc, and colleagues clearly demonstrated that Müller glia can retain their normal, metabolic support functions even while proliferating (Vazquez-Chona et al, 2011). This study showed that conditional ablation of the cyclin-dependent kinase inhibitor, p27 kip1 , with the tamoxifen-regulated CreER-loxP system, produced a gliotic response in retinal Müller glia – hypertrophy, increased expression of GFAP, reentry into the cell cycle, and apically displaced nuclei – in the absence of retinal injury.…”

Reactive Muller Glia as Potential Retinal Progenitors

“…Hypertrophic glia help to form and maintain a barrier around injured tissue which helps to protect surrounding tissues from inflammatory signals [136,137]. On one hand, there is evidence that the increased production of GFAP does not lead to diminished neuronal metabolism, eletrophysiology or visual function [138]. However, evidence from injured spinal cord indicates axonal regeneration and functional recovery was increased in GFAP/vimentin double-knockouts in comparison to wild type controls [139].…”

“…P27 regulates the cell cycle by blocking cell cycle progression into the S-phase, and hence is necessary for maintainance of the quiescent state [182]. Knock-out mice for p27 show many of the characteristics of reactive gliosis, including an increase in GFAP expression and proliferation and migration of cells into the subretinal space [138,[182][183][184].…”