The impact of Cyclin D1 on proliferating cells in the intact and injured mouse cortex

Abstract

Cell proliferation is an essential component of brain formation and homoeostasis, tightly regulated by cell cycle proteins. The members of the cyclin D family are responsible for the initiation of the cell cycle and thus key regulators of the cell cycle. Mammals posess three isoforms of Cyclin D (D1, D2 and D3). It has been shown, that injury to the adult brain leads to a substantial increase of local Cyclin D1 expression. This upregulation has been associated with the apoptosis of neurons, but also with the proliferation of glial cells, which contribute to the glial scar formation and to the inflammatory reaction. Subsequent treatment with pharmacological inhibitors of the Cyclin D1-dependent pathway have shown to decrease injury-induced lesion volume and glial scar formation, suggesting that modulation of cell cycle might be beneficial for the injury outcome. In this study, I took advantage of mice genetically deficient in the Cyclin D1 gene to study its function in proliferating cells of the intact and injured cortex. I could show that the postnatal proliferation of microglia is completely impaired by the absence of Cyclin D1. In contrast, the proliferation of oligodendrocyte progenitor cells (OPCs) was independent of Cyclin D1 at early postnatal stages and only reduced during adult stages. This finding suggests a switch in the requirement for distinct cell cycle proteins driving proliferation of OPCs during development and in the adult. Using an injury model leading to local neurodegeneration, I could show that the deficiency for Cyclin D1 reduces the size of the lesion three days following insult to the adult brain cortex. In parallel, the injury-induced Proliferation was significantly reduced within the lesion site. A closer examination of the glial cell types within the neurodegenerative area revealed that the proliferation of microglia and OPCs was impaired in the Cyclin D1 knockout animals. Finally, I provided evidence that Cdk4 but not Cdk2 or Cdk6 are required for injury-induced proliferation of OPCs thus indicating Cdk4 most likely to be the interaction partner of Cyclin D1.