The complex morphology of reactive astrocytes controlled by fibroblast growth factor signaling

Abstract

Astrocytes are the most abundant cell-type of the human brain and play a variety of roles in brain homeostasis and synaptic maturation, under normal conditions. However, astrocytes undergo dramatic pathological changes in response to brain injury, such as reactive gliosis and glial scar formation. Although abnormal hypertrophy and massive proliferation of astrocytes are obvious, the molecular identity and cues that dictate the structural changes in reactive astrocytes remain unclear. This study proposes that fibroblast growth factor (FGF) signaling is responsible for making astrocyte morphology more complex and hypertrophic in response to an inflammatory stimulus such as lipopolysaccharide. Primary astrocytes isolated from perinatal brains developed more branches in the presence of FGF8 or lesser branches in the presence of FGF2. Introduction of the constitutively active form of the FGF receptor 3 (caFGFR3) into the brain increases the structural complexity, with greater glial fibrillary acidic protein level in astrocytes, while overexpression of a dominant-negative form of FGFR3 (dnFGFR3) reduces it. Treatment of FGF8 facilitated the wound-healing process of primary astrocytes in vitro by changing their morphology, indicating that the FGF signal may control the responsiveness of astrocytes in injury conditions. Finally, the blockade of FGF signaling by introducing dnFGFR3 at the site of reactive gliosis reduces astrocyte branch formation and minimizes hypertrophic responses during reactive gliosis. Taken together, these results indicate that FGF8-FGFR3 signaling controls structural changes in astrocytes during reactive gliosis, under pathogenic conditions.

Dysregulation of astrocyte extracellular signaling in Costello syndrome

“…These results support the hypothesis that increased number or volume of glia may contribute to the increased brain size commonly observed in patients with RASopathies (31). The altered morphology that we observed is consistent with recent reports that FGF signaling, which acts through Ras signaling and other receptor tyrosine kinases (35), controls astrocyte complexity and morphology (65, 66). We then determined the consequences of this early Ras-specific maturation upon neuronal function.…”

FGF2 alleviates PTSD symptoms in rats by restoring GLAST function in astrocytes via the JAK/STAT pathway

“…Secondary astrocytes with a purity of 95% were used in the following experiments. The cells were administrated of FGF2 (30 ng/ml) and AG490 (50 μM) for 48 h based on the previous reports, respectively (Kandalam et al, 2012;Kang et al, 2014).…”

Neuronal mTORC1 Is Required for Maintaining the Nonreactive State of Astrocytes

“…mTORC1 Regulates Neuron-derived FGF-2 to Suppress Reactive Astrogliosis-Because it has been suggested that FGF signaling may be necessary for controlling astrocyte morphology and activation (31), one possibility is that extracellular FGF-2 reacts with the FGF-2 receptor on astrocytes in Raptor nKO mice. To confirm the regulation of FGF-2 by mTORC1, we verified the transcriptional levels of FGF-2 and other crucial FGF family members (32) in neurons cultured from mutant or wild type mice.…”