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Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014 Apr 16;82(2):380-97. PubMed.
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Stanford University
This paper nicely demonstrates the dependence of postnatal microglia on CSF1R for survival, using an inhibitor from Plexxikon currently in clinical trials to treat non-Hodgkin lymphoma. While CSF1R-deficient mice fail to produce microglia and other myeloid lineage cells and eventually cause early postnatal death, it was unclear how sensitive microglia are to selective CSF1R inhibition. In addition, as also nicely demonstrated recently by Wenbiao Gan's group at New York University, and others, Green's group shows that microglia repopulate from cells within the CNS after ablation. However, this paper falls short in determining whether microglia repopulate in this case from progenitors (non-microglia cells with robust potential to become microglia) or rapidly proliferating microglia. The evidence for the first and against the second is largely correlative—and further studies are required to isolate and demonstrate the progenitor potential of putative microglia progenitor cells.
Indiana University School of Medicine
The new work from Kim Green’s lab is remarkable and provides several important insights into microglial biology. The most dramatic finding from this study is the discovery that virtually all adult microglia are entirely reliant upon CSF1R signaling for their survival. While the requirement for CSF1R activation was recognized developmentally, previous attempts to evaluate its role in the adult brain yielded less impressive results. The ready availability of a blood-brain-barrier-permeant drug to rapidly and selectively eliminate this cell type provides an important new tool. The most striking finding in this study is the observation that upon removal of the drug, the brain rapidly establishes its microglia population with normal tiling densities. The discovery of a proliferating, nestin-positive microglial progenitor that also expresses hematopoietic stem-cell markers in the adult brain and that appears between two and three days following drug withdrawal is striking and unexpected. The characterization of this progenitor and identification of the factors driving its genesis of microglia is of substantial importance and interest. It should be noted that Varvel et al. found that elimination of microglia using a CD11b-TK/ganciclovir approach resulted in repopulation of the brain by peripheral monocytes and not from cells endogenous to the brain at twice the normal tiling density. Recently, Parkhurst et al. depleted microglia in the adult brain by expressing the diphtheria toxin receptor selectively in these cells followed by diphtheria toxin administration. In this latter case no repopulation was observed. The basis for these widely varied experimental outcomes remains unexplained, but highlights the complex influences and dynamics involved in maintaining and occupying these myeloid niches in the mature brain.
Green and colleagues reported that mice in which microglia had been depleted were behaviorally intact, as evaluated in a number of different tasks, even over a period of several months. This finding is quite different from that reported by Parkhurst et al., who found that learning a new motor skill was impaired in microglial-depleted mice, which also had impaired performance in a fear-conditioning assay and a novel-object-recognition task. Undoubtedly, resolution of this basis for these different experimental outcomes will be a high priority. Clearly, the extension of these approaches to evaluate microglial actions in disease models is an obvious next step and these experiments are likely to be underway.
Overall, this is an important paper from a dynamic young investigator who has made fundamental new discoveries. The biology of microglia is evolving at prodigious speed and in ways no one might have expected.
References:
Varvel NH, Grathwohl SA, Baumann F, Liebig C, Bosch A, Brawek B, Thal DR, Charo IF, Heppner FL, Aguzzi A, Garaschuk O, Ransohoff RM, Jucker M. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18150-5. PubMed.
Eng H, Robertson JA, Stemke GW. Effects of anti-Ureaplasma urease antibody on homologous and heterologous urease activities. Microbios. 1987;49(198):47-54. PubMed.
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