ABSTRACT
Despite the vast abundance of glial progenitor cells in the mouse brain parenchyma, little is known about the molecular mechanisms driving their proliferation in the adult. Here we unravel a critical role of the G1 cell cycle regulator cyclin D1 in controlling cell division of glial cells in the cortical grey matter. We detect cyclin D1 expression in Olig2-immunopositive (Olig2+) oligodendrocyte progenitor cells, as well as in Iba1+ microglia and S100ß+ astrocytes in cortices of 3-month-old mice. Analysis of cyclin D1-deficient mice reveals a cell and stage-specific molecular control of cell cycle progression in the various glial lineages. While proliferation of fast dividing Olig2+ cells at early postnatal stages becomes gradually dependent on cyclin D1, this particular G1 regulator is strictly required for the slow divisions of Olig2+/NG2+ oligodendrocyte progenitors in the adult cerebral cortex. Further, we find that the population of mature oligodendrocytes is markedly reduced in the absence of cyclin D1, leading to a significant decrease in the number of myelinated axons in both the prefrontal cortex and the corpus callosum of 8-month-old mutant mice. In contrast, the pool of Iba1+ cells is diminished already at postnatal day 3 in the absence of cyclin D1, while the number of S100ß+ astrocytes remains unchanged in the mutant.
Subject(s)
Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Cyclin D1/biosynthesis , Neuroglia/metabolism , Stem Cells/metabolism , Age Factors , Animals , Animals, Newborn , Cell Division/physiology , Cerebral Cortex/growth & development , Female , Male , Mice , Mice, KnockoutABSTRACT
Little is known about the molecular mechanisms driving proliferation of glial cells after an insult to the central nervous system (CNS). To test the hypothesis that the G1 regulator cyclin D1 is critical for injury-induced cell division of glial cells, we applied an injury model that causes brain damage within a well-defined region. For this, we injected the neurotoxin ibotenic acid into the prefrontal cortex of adult mice, which leads to a local nerve cell loss but does not affect the survival of glial cells. Here, we show that cyclin D1 immunoreativity increases drastically after neurotoxin injection. We find that the cyclin D1-immunopositive (cyclin D1+) cell population within the lesioned area consists to a large extent of Olig2+ oligodendrocyte progenitor cells. Analysis of cyclin D1-deficient mice demonstrates that the proliferation rate of Olig2+ cells diminishes upon loss of cyclin D1. Further, we show that cyclin-dependent kinase (cdk) 4, but not cdk6 or cdk2, is essential for driving cell division of Olig2-expressing cells in our injury model. These data suggest that distinct cell cycle proteins regulate proliferation of Olig2+ progenitor cells following a CNS insult.
Subject(s)
Adult Stem Cells/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Brain Injuries/pathology , Cell Proliferation , Cerebral Cortex/pathology , Cyclin D1/metabolism , Gene Expression Regulation/physiology , Nerve Tissue Proteins/metabolism , Analysis of Variance , Animals , Bromodeoxyuridine , Cell Proliferation/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cyclin D1/deficiency , Cyclin-Dependent Kinase 2/deficiency , Cyclin-Dependent Kinase 4/deficiency , Cyclin-Dependent Kinase 6/deficiency , Disease Models, Animal , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Ibotenic Acid/toxicity , In Situ Nick-End Labeling , Mice , Mice, Knockout , Neurotoxins/toxicity , Oligodendrocyte Transcription Factor 2 , Time FactorsABSTRACT
In both insects and mammals, second-order olfactory neurons receive input from olfactory receptor neurons and relay olfactory input to higher brain centers. In Drosophila, the wiring specificity of these olfactory projection neurons (PNs) is predetermined by their lineage identity and birth order. However, the genetic programs that control this wiring specificity are not well understood. The cephalic gap gene empty spiracles (ems) encodes a homeodomain transcription factor required for embryonic development of the antennal brain neuromere. Here we show that ems is expressed postembryonically in the progenitors of the two major olfactory PN lineages. Moreover, we show that ems has cell lineage-specific functions in postembryonic PN development. Thus, in the lateral PN lineage, transient ems expression is essential for development of the correct number of PNs; in ems mutants, the number of PNs in the lineage is dramatically reduced by apoptosis. By contrast, in the anterodorsal PN lineage, transient ems expression is necessary for precise targeting of PN dendrites to appropriate glomeruli; in ems mutants, these PNs fail to innervate correct glomeruli, innervate inappropriate glomeruli, or mistarget dendrites to other brain regions. Furthermore, in the anterodorsal PN lineage, ems controls the expression of the POU-domain transcription factor Acj6 in approximately half of the cells and, in at least one glomerulus, ems function in dendritic targeting is mediated through Acj6. The finding that Drosophila ems, like its murine homologs Emx1/2, is required for the formation of olfactory circuitry implies that conserved genetic programs control olfactory system development in insects and mammals.
