In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss-and gainof-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.brain damage | astrogliosis A strocytes are the most abundant cell type in the mammalian brain. The thin processes of protoplasmic astrocytes (graymatter astrocytes) canvas the neural parenchyma and make contact with several other cell types. Protoplasmic astrocytes carry out a variety of functions, including maintaining the bloodbrain barrier, ion homeostasis, neurotransmitter turnover, and synapse formation (1). Another major function of these astrocytes involves their activation in response to damage. Astrocyte activation, or astrogliosis, plays a central role in the response to most or all neurological insults including trauma, infections, stroke, tumorigenesis, neurodegeneration, and epilepsy. The extent of astrogliosis can influence long-term recovery, and the response of astrocytes to different insults is likely to be graded and complex (2, 3). Nevertheless, in most cases, astrocytes transiently become hypertrophic and express high levels of intermediate filaments such as GFAP, vimentin, tenascin C, and nestin, and, in cases of severe damage, astrocytes can also become proliferative and form a scar.Astrogliosis can have beneficial and detrimental effects on recovery. Astrogliosis is essential for minimizing the spread of damage and inflammation, but it is also inhibitory for axonal and cellular regeneration. For example, in transgenic mice in which reactive astrocytes are ablated or disabled, traumatic injury leads to the lack of normal scar formation, prolonged and more widespread inflammation, and a failure to reconstruct the bloodbrain barrier and maintain tissue integrity (4, 5). However, ablation or impairment of reactive astrocytes also leads to increased nerve fiber growth in the immediate vicinity of the injury site, which could improve axonal regeneration and functional recovery (4, 5). Therefore, levels of astrocy...

Reactive astrocytes are associated with a vast array of central nervous system (CNS) pathologies. The activation of astrocytes is characterized by changes in their molecular and morphological features, and depending on the type of damage can also be accompanied by inflammatory responses, neuronal damage, and in severe cases, scar formation. Although reactive astrogliosis is the normal physiological response essential for containing damage, it can also have detrimental effects on neuronal survival and axon regeneration, particularly in neurodegenerative diseases. It is believed that progressive changes in astrocytes as they become reactive are finely regulated by complex intercellular and intracellular signaling mechanisms. However, these have yet to be sorted out. Much has been learned from gain-of-function approaches in vivo and culture paradigms, but in most cases, loss-of-function genetic studies, which are a critical complementary approach, have been lacking. Understanding which signaling pathways are required to control different aspects of astrogliosis will be necessary for designing therapeutic strategies to improve their beneficial effects and limit their detrimental ones in CNS pathologies. In this article, we review recent advances in the mechanisms underlying the regulation of aspects of astrogliosis, with the main focus on the signaling pathways that have been studied using loss-of-function genetic mouse models. Keywords Astrogliosis; Gliosis; Reactive gliosis; GeneticsThe CNS is susceptible to many types of pathological insults such as traumatic injury, ischemia, neurotoxic chemicals, tumors, infections, and neurodegenerative diseases. In all these cases, the response to damage includes at a minimum the activation of astrocytes, characterized by changes in their morphology and molecular expression profile. In addition to these changes, the response to damage often includes increased proliferation of several cell types, infiltration of leukocytes, scar formation, and neuronal death [1][2][3][4]. In this review, we limit our discussion primarily to what molecular mechanisms regulate astrocyte activation.Many cell types including neurons, microglia, oligodendrocytes, endothelial cells, and leukocytes are likely to interact with astrocytes and influence the duration and amount of reactive astrogliosis [1][2][3]5]. Although many extracellular signals are known to be upregulated in different CNS pathologies, the cells that produce or respond to these signals in vivo in each case and how these signals affect astrocytes in particular is poorly understood.

During corticogenesis, the balance between the self renewal of radial glial stem cells and the production of their descendent progenitor cells is essential in generating the correct size and cell composition of the neocortex. How the stem to progenitor cell transition is regulated is poorly understood. FGFs are commonly implicated in promoting proliferation of neural precursor cells, but it is unclear how they exert their effects on stem cells, progenitor cells, or both in vivo. Here, three FGF receptor genes are simultaneously deleted during cortical neurogenesis. In these mutants, radial glia are depleted due to an increased transition from an uncommitted state to a more differentiated one, initially causing an increase in progenitors, but ultimately resulting in a smaller cortex. The proliferation rate of progenitors themselves, however, is unchanged. These results indicate that FGFs normally repress the radial glia to progenitor cell transition during corticogenesis.

The mechanisms regulating hippocampal neurogenesis remain poorly understood. Particularly unclear is the extent to which age-related declines in hippocampal neurogenesis are due to an innate decrease in precursor cell performance or to changes in the environment of these cells. Several extracellular signaling factors that regulate hippocampal neurogenesis have been identified. However, the role of one important family, FGFs, remains uncertain. Although a body of literature suggests that FGFs can promote the proliferation of cultured adult hippocampal precursor cells, their requirement for adult hippocampal neurogenesis in vivo and the cell types within the neurogenic lineage that might depend on FGFs remain unclear. Here, specifically targeting adult neural precursor cells, we conditionally express an activated form of an FGF receptor or delete the FGF receptors that are expressed in these cells. We find that FGF receptors are required for neural stem-cell maintenance and that an activated receptor expressed in all precursors can increase the number of neurons produced. Moreover, in older mice, an activated FGF receptor can rescue the age-related decline in neurogenesis to a level found in young adults. These results suggest that the decrease in neurogenesis with age is not simply due to fewer stem cells, but also to declining signals in their niche. Thus, enhancing FGF signaling in precursors can be used to reverse age-related declines in hippocampal neurogenesis.

The high-mobility-group (HMG) box is a conserved DNA-binding domain found in a family of transcription factors that regulate growth and development. One family member, Ste11p, directs sexual differentiation of Schizosaccharomyces pombe by binding specific DNA sequences upstream of genes required for mating and meiosis. Here, we show that Ste11p is a shuttling protein. In growing cells, Ste11p is present in low levels and is pancellular. Mating pheromones and nutrient limitation trigger nuclear accumulation and increased expression of the transcription factor. Several mechanisms likely control Ste11p localization. First, the 14-3-3 protein, Rad24p, binds phosphorylated Ste11p and inhibits its nuclear accumulation. Second, the HMG domain of Ste11p contains a basic cluster nuclear localization signal. Finally, treatment of cells with leptomycin B, an exportin inhibitor, results in the nuclear accumulation of Ste11p. A Ste11p deletion mutation, ⌬C54, mimics the effects of leptomycin B. The C54 region contains no identifiable nuclear export signal but instead is required for biological activity and to stimulate Ste11p target gene expression. These results provide evidence that both nuclear import and export mechanisms operate to regulate cellular localization of an HMG box protein. In addition, they establish a paradigm for the potential role of pheromone/hormone-like polypeptides in cellular localization of this important class of developmental regulators.