Novel Astrocyte-Specific Transgenic Mice Identify Distinct Populations of Transient Amplifying Progenitor Cells And Long-Lived Neural Stem Cells In the Subgranular Zone of the Adult Mouse Brain




Boies, Lori Nicole Loomis

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A lack of previous interest in the astrocyte biology field has resulted in a meager number of astrocyte specific molecular markers and practical protocols to study their biology and function. The most common and accepted astrocyte marker is glial fibrillary acidic protein (GFAP), but in normal, healthy adult brains, GFAP expression is limited to the neurogenic regions, white matter tracks, and pia. This limited expression is not a true representation of astrocyte distribution patterns and does not account for astrocyte heterogeneity. Through a careful screen, cystatin C (CstC) and phospholipase A2 Group VII (PLA2G7) were identified as astrocyte specific molecular markers. To study the role of these genes in astrocyte biology, inducible CreERT2 mice were generated. Using the CstC-CreERT2 and PLA2G7-CreERT2 mouse lines, in concert with the Rosa26YFP reporter line, cell fate tracking experiments were performed in both embryonic and adult time points in tandem with extensive immunohistochemistry. Both astrocyte-specific CreERT2 lines demonstrated limited expression in embryos as early as embryonic day 12.5 and extensive expression throughout the entire central nervous system in all adult time points analyzed. In adult animals, both CstC-CreERT2 and PLA2G7-CreERT2 Rosa26YFP positive cells had strong expression in both neurogenic niches. Using careful quantification and immunohistochemistry colocalization, the dynamics of these transgenic lines were meticulously researched in the subgranular zone (SGZ) of the dentate gyrus. The CstC-CreERT2/Rosa26YFP cells represent a transient amplifying compartment in the SGZ while PLA2G7-CreERT2/Rosa26YFP positive cells comprise a long-lived neural stem cell compartment. Discovery of these astrocyte dynamics in the SGZ complements the literature indicating astrocytes are the true neural stem cells and adds knowledge of new viable markers and cell populations to the field. Results of these studies reveal not only new molecular markers for astrocytes in both embryonic and adult scenarios, but also help to identify the underlying heterogeneity of astrocyte populations, as well as adult neural stem cells. Future utilization of these inducible transgenic mouse models could provide the potential to study both astrocyte and neural stem cell pathophysiologies.

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