Reactive astrocytes responding to pathological insults are distinct from normal astrocytes in morphology, functions and molecular profiles [1, 5–7]. To explore these astrocytes’ regulatory mechanisms, many molecules have been investigated over the past few decades. However, many of them exhibit paradoxical implications [5–7]. Further complicating the picture is the fact that the regulatory mechanisms of reactive gliosis have been most frequently studied in cell culture models. Findings from such models are increasingly being tested in genetically engineered mice, with some studies failing to confirm in vitro findings in vivo. For example, cytoplasmic or nuclear signaling proteins, such as Akt, mechanistic target of rapamycin, extracellular signal-regulated kinase (Erk) and signal transducer and activator of transcription 3 (STAT3), are upregulated in reactive astrocytes, and their positive involvement in regulating astrogliosis has been confirmed by genetic approaches in vivo [8–14]. Receptor tyrosine kinases are upstream activators of these signaling pathways [15–17]. Among these, fibroblast growth factor 2 (FGF2) and its receptor (FGFR) increase in reactive astrocytes, promote GFAP expression in cultured astrocytes, and are thus thought to mediate astrocytes’ reactive responses. Surprisingly, recent loss- and gain-of-function studies on genetically engineered mice show that FGF signaling inhibits astrocyte reactivity under both uninjured and injured conditions . These findings emphasize that the upstream signaling that regulates astrogliosis remains largely undetermined.