Conditional deletion of β1‐integrin in astroglia causes partial reactive gliosis

Abstract

Astrocytes play many pivotal roles in the adult brain, including their reaction to injury. A hallmark of astrocytes is the contact of their endfeet with the basement membrane surrounding blood vessels, but still relatively little is known about the signaling mediated at the contact site. Here, we examine the role of beta1-integrin at this interface by its conditional deletion using different Cre lines. Thereby, the protein was reduced only at postnatal stages either in both glia and neurons or specifically only in neurons. Strikingly, only the former resulted in reactive gliosis, with the hallmarks of reactive astrocytes comprising astrocyte hypertrophy and up-regulation of the intermediate filaments GFAP and vimentin as well as pericellular components, such as Tenascin-C and the DSD-1 proteoglycan. In addition, we also observed to a certain degree a non-cell autonomous activation of microglial cells after conditional beta1-integrin deletion. However, these reactive astrocytes did not divide, suggesting that the loss of beta1-integrin-mediated signaling is not sufficient to elicit proliferation of these cells as observed after brain injury. Interestingly, this partial reactive gliosis appeared in the absence of cell death and blood brain barrier disturbances. As these effects did not appear after neuron-specific deletion of beta1-integrin, we conclude that beta1-integrin-mediated signaling in astrocytes is required to promote their acquisition of a mature, nonreactive state. Alterations in beta1-integrin-mediated signaling may hence be implicated in eliciting specific aspects of reactive gliosis after injury.

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

“…Deletion of β-integrin in embryonic astrocytes results in astrocyte activation in postnatal mice, and deletion of Smoothened, a mediator of SHH signaling, at early postnatal stages leads to features of astrogliosis in the adult forebrain (8,9). It remains unclear whether other factors are also required to actively maintain the nonreactive state of cortical astrocytes under normal conditions or to regain their nonreactive state when damage has been contained.…”

“…Attenuation of Sonic Hedgehog (SHH) signaling in postnatal astrocytes leads to increased astrocytic GFAP expression in the absence of an induced injury, suggesting a role for SHH in suppressing the activation of astrocytes (8). Deletion of β-integrin in embryonic astrocytes also results in their postnatal activation, although, in this case, an indirect developmental defect could not be excluded (9). Nevertheless, the extent to which factors actively maintain astrocytes in a nonreactive state in the healthy brain or after injury to resolve their response remains unclear.…”

Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential

“…For instance, disruption of the contact between astrocyte endfeets and vascular basement membranes by astroglia specific deletion of integrin β1, triggers a partial reactive state, including hypertrophy, GFAP, vimentin and Tenascin-C upregulation but excluding proliferation [69]. Other contact-related regulators of astrogliosis are Ephrins (Ephs) and their receptors [70].…”

Genetic Deletion ofCdc42Reveals a Crucial Role for Astrocyte Recruitment to the Injury SiteIn VitroandIn Vivo

“…F, Measurements of protrusion and cell length were done. the uninjured brain in vivo (Robel et al, 2009), and interference with integrin signaling in astrocytes in vitro blocks protrusion formation and polarity (EtienneManneville and Hall, 2001;Osmani et al, 2006;Peng et al, 2008). Notably, in vivo, palisading zone formation and bipolar orientation could also occur in the absence of ␤1-integrins in astrocytes (data not shown), further supporting the concept of alternative pathways in astrocyte orientation in vitro (requiring ␤1-integrins and Cdc42) and in vivo (not requiring either of these).…”

“…Astrocytes are polarized toward the basement membrane around blood vessels and target proteins, such as aquaporin-4 to their endfeet (Bragg et al, 2006). If this interface fails to form properly, as is the case following a loss of ␤1-integrins, there results a mild reactive gliosis with all hallmarks of reactive astrogliosis except proliferation (Robel et al, 2009), highlighting the importance of astrocyte polarity. However, little is known about the role of astrocyte polarity after brain injury in vivo.…”