Slit and glypican‐1 mRNAs are coexpressed in the reactive astrocytes of the injured adult brain

Abstract

The slit family serves as a repellent for growing axons toward correct targets during neural development. A recent report describes slit mRNAs expressed in various brain regions in adult rats. However, their functions in the adult nervous system remain unknown. In the present study, we investigated whether slit mRNAs were expressed in the cryo-injured brain, using in situ hybridization. All slit family members were expressed at the lesion. Slit2 mRNA was the most intensely expressed in the cells surrounding the necrotic tissue. A double-labeling study showed that slit2 mRNA was expressed in the glial fibrillary acidic protein (GFAP)-positive reactive astrocytes. In addition, glypican-1, a heparan sulfate proteoglycan that serves as a high-affinity receptor for Slit protein, was coexpressed with slit2 mRNA in the reactive astrocytes. These findings suggested that slit2 might prevent regenerating axons from entering into the lesion in concert with glypican-1.

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

“…An analogous negative role on axonal growth has been shown for scar Ephrins, namely EphA4, whose deletion, besides attenuating reactive gliosis and scar formation, allows axon growth and functional improvement in injured animals [70]. Similarly, the expression of Slit modulators of axon guidance increases in reactive astrocytes [108] and may contribute to regeneration failure. Finally, other scar inhibitory elements such as Semaphorin 3A, produced by meningeal fibroblasts reacting to damage [109], and the cell adhesion molecule Tenascin R, upregulated and secreted by astrocytes after lesion, may act as barriers to tissue recovery [119,111].…”

Studies on the Development and Behavior of the Dystrophic Growth Cone, the Hallmark of Regeneration Failure, in anIn VitroModel of the Glial Scar and after Spinal Cord Injury

“…Importantly, our data suggest that it may not simply be the excess of inhibitory matrices at CNS lesions that leads to regeneration failure and dystrophy but, rather, that their distribution in a gradient transforms the growth cone into a state that is apparently incapable of freeing itself from the lesion environment. Finally, it should be noted and stressed that although we have learned that an appropriately crafted aggrecan gradient in combination with laminin is sufficient to create growth cone dystrophy in an in vitro setting, we do not yet know what roles other potential inhibitors, such as semaphorins, ephrins, slits, and other types of proteoglycans, which are all present in the scar and could also be patterned in a gradient (Zhang et al, 1997;Miranda et al, 1999;De Winter et al, 2002;Bundesen et al, 2003;Hagino et al, 2003;Tang et al, 2003), may play in triggering the dystrophic state in vivo. We now look toward developing and screening possible therapies that allow would-be dystrophic axons to regenerate robustly past the outermost rim in our glial scar model and then determining whether the optimal strategy translates in vivo.…”

Regeneration beyond the glial scar

“…Slit proteins, which are important regulators of axon guidance and cell migration (reviewed by Brose and Tessier-Lavigne 90 ), are also increased, along with their glypican 1 receptors 91 , in reactive astrocytes after cortical injury 92 . These observations have caused the Slit proteins to be implicated in regeneration failure.…”