| Abstract No.: | C-A3019 |
| Country: | Canada |
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| Title: | A ROLE FOR MICROGLIA DURING NEURODEVELOPMENTAL DISORDERS |
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| Authors/Affiliations: | 1 Joseph Antony*; 1 David Kaplan; 1 Freda Miller;
1 SICKKIDS, Toronto, ON, Canada
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| Content: | Microglia are resident hematopoietic cells that play a key role in neurodegeneration and neural injury in the adult nervous system. However, apart from a role in developmental cell death, the role of microglia in normal brain development remains an open question. We have asked whether microglia regulate the development of embryonic cortical precursors during normal or perturbed development. Analysis of the embryonic brain showed that microglia are present in regions that contain neural precursors from E11 onward, and that approximately 0.2% of cells in the E13 cortex are microglia. Depletion of these microglia from cortical precursor cultures using a FACS-based approach demonstrated that these microglia are essential for the normal genesis of neurons and glial cells. Thus, microglia are essential for normal cortical precursor development, at least in culture. We are currently asking whether they are also essential in vivo using a mutant mouse that lacks cells of the macrophage/microglial lineage. To ask whether microglia are also important in neural developmental disorders, we have focused upon Noonan Syndrome (NS), a genetic disorder where the SHP2 tyrosine protein phosphatase is aberrantly activated. Microglial numbers are increased approximately 4-fold in the developing NS brain, likely because increased SHP2 activity directly promotes microglial proliferation. This 4-fold increase in microglial number is sufficient to perturb neural precursor development: a similar increase in microglia in E12.5 cortical precursor cultures caused enhanced gliogenesis and perturbed neurogenesis. Thus, our results suggest that microglia are necessary for normal cortical precursor development, and that increases in microglia as a consequence of genetic or pathological events would directly perturb neural development by affecting neural precursor development. |
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