UC Riverside

In the healthy brain, astrocytes function as key homeostatic players that support neuronal signaling, communicate with the blood brain barrier to maintain its selective permeability, and participate in the glymphatic system to ensure proper waste removal. Astrocytes were originally named nervenkitt, or neuronal glue and were considered to be homogenous and physiologically inactive cells, providing little more than structural support. Recently we have begun to understand the dynamic and diverse roles these cells occupy. As the importance of astrocytes has come into focus, so has the need to understand the mechanisms that drive their development. Here, we review current understanding of the developmental processes that give rise to the mature astrocyte and produce diverse astrocyte populations. We will also look at the commonalities that developing astrocytes share with another process, astrocyte reactivity. In response to immune challenges, astrocytes become reprogramed into reactive astrocytes in a process known as reactive gliosis. Reactive astrocytes are commonly identified by upregulation of intermediate filaments and hypertrophy. The mechanisms underlying reactivity and the functions that it serves are yet to be fully understood. Currently, there are a lack of tools which allow us to specifically target astrocytes after they become reactive. Studies characterizing reactivity have revealed several genes expressed in astrocytes only after the brain is immune challenged. Using this knowledge, we developed a transgenic mouse that expresses Cre recombinase under the promoter of one of the identified markers, Lcn2 (Lcn2CreErt2). The Lcn2CreErt2 mouse was validated across a variety of disease models including systemic inflammation and parasitic infection. We used this mouse to drive the permanent expression of a fluorescent marker, which allowed us to observe changes in reactive gene expression during and after the resolution of inflammation. In order to address potential off target effects of Lcn2CreErt2, we developed viruses that drive expression of Cre dependent genes under the GFAP promoter. We were also able to use the Lcn2CreErt2 mouse to isolate labeled cells through flow cytometry. The experiments performed represent only a fraction of the possibilities for the ways the Lcn2CreErt2 mouse will enhance our understanding of reactive astrocytes.