Expression of Cyclin-D1 in Astrocytes Varies During Aging.

Brigitte Ciapa,Sylvie Granon

doi:10.3389/fnagi.2018.00104

Abstract

D-Cyclins control progression through the G1 phase and the G1/S transition of the cell cycle. In the adult brain, they regulate neurogenesis which is limited to the sub-granular zone of the dentate gyrus (DG) and to the sub-ventricular zone (SVZ) of the lateral ventricles. Yet, D-cyclins have also been detected in other parts of the adult brain in differentiated neurons that do not proliferate and rather die by apoptosis in response to cell cycle reactivation. Expression of D-cyclins in astrocytes has also been reported but published results, such as those concerning neurons, appear conflictual. We carried out this study in order to clarify the general pattern of D-cyclin expression in the mouse brain. By performing GFAP/cyclin-D1 double labeling experiments, we detected hypertrophic astrocytes expressing cyclin-D1 in their cytoplasmic processes. Their number increased with age in the hippocampus area but decreased with age in the SVZ. Clusters of astrocytes expressing cyclin-D1 were also detected in the cortical areas of old mice and around blood vessels of neurogenic areas. Other non-asteroidal small cells, probably stem cells, expressed both GFAP and nuclear cyclin-D1 in the neurogenic area of the DG and in the SVZ at a higher density in young mice than in old mice. Finally, cells expressing cyclin-D1 but not GFAP were also found scattered in the striatum and the CA1 region of the hippocampus, and at a high percentage in cortical layers of young and old mice. Our results suggest that astrocytes may control neuronal functions and proliferation by modulating, in normal or altered conditions such as aging or degenerative diseases, cyclin-D1 expression.

Highlights

D-Cyclins belong to the family of cyclin-dependent kinases (CDKs)/cyclin complexes which regulate the cell cycle in all eukaryotes (Malumbres and Barbacid, 2009; Tyson and Novák, 2015)
The presumed identity of these cells as astrocytes led us to ask the following questions: do astrocytes normally express cyclin-D1 and, if this is the case and since we found these clusters in a 1 year old mouse, would it be related to aging? By performing GFAP/cyclin-D1 double labeling experiments, we confirmed the presumed identity of asteroidal cells expressing cyclin-D1 as being astrocytes in cortical areas of aged mice
We suggest that astrocytes may modulate neuronal functions, in normal and/or in altered conditions such as aging or degenerative diseases, by mechanisms implying cyclin-D1 expression

Summary

Introduction

D-Cyclins belong to the family of cyclin-dependent kinases (CDKs)/cyclin complexes which regulate the cell cycle in all eukaryotes (Malumbres and Barbacid, 2009; Tyson and Novák, 2015). These cell-cycle independent functions of Cdks in brain are mostly related to Cdk kinase, which is an unconventional member of the Cdk-family (reviewed by Su and Tsai, 2011; Lim and Kaldis, 2013) Their activity changes when neuronal functions are modified, during stress, normal training, or neurological disorders (Kawauchi et al, 2013; Frade and Ovejero-Benito, 2015; Lieberwirth et al, 2016). Neural aging often triggers aberrant entry into the cell cycle (Sarlak et al, 2013; Chow and Herrup, 2015) and mediates oxidative stress responses, mitochondrial dysfunction and DNA damage in various animals, from worms and flies to mice and humans (Bishop et al, 2010) In these processes, the activity of D-cyclins-CdK4/6 must be blocked in the case of DNA damage, to allow for repair and to prevent proliferation, as demonstrated in Drosophila by Icreverzi et al (2015)

Methods

Results

Conclusion