11 Jul 2003

Recent evidence has enhanced the image of astrocytes, suggesting these glial cells are a source for stem cells (see ARF related news story), and that they mop up Aβ (see ARF related news story). But online publications in this week's PNAS and Nature Neuroscience indicate that astrocytes also are a major impediment to axon repair and to the integration of transplanted tissue into the neural circuitry.

Writing in PNAS, M. Gimenez y Ribotta and colleagues from the University of Montpellier, France, report that transgenic mice lacking two key astrocyte genes are much better at repairing severed spinal cords. The genes, coding for two components of astrocytic filaments, glial fibrillary acidic protein (GFAP), and vimentin, appear essential for normal astrocyte movement and function. This implies that astrocytes cannot build the “glial scar”-long known to form a barrier to axonal regeneration-without these two components of their cytoskeleton. It deepens molecular insight into this “other” impairment to repair (the better-understood one being the inhibitory molecules found on the surface of oligodendrocytes).

First author V. Menet and colleagues show that, after spinal cord lesion, the double-knockout mice actually recover function. These animals had only about a third as many mobility problems as did wild-type animals with the same lesion. Furthermore, while both sets of animals exhibited similar locomotor problems immediately after the lesion, wild-type animals continued to decline. whereas double KOs recovered function.

Menet and colleagues observed that, in the wild-type animals, cells testing positive for the astrocyte marker nestin were abundant in the vicinity of the lesion up to five weeks after the injury. Far fewer astrocytes gathered around the lesion in double KOs, and were almost undetectable after five weeks. As for reinnervation, the authors observed little difference between wild-type and single GFAP or vimentin knockouts, but the double knockouts had significantly higher numbers of serotonin-positive fibers, equivalent to 78 percent innervation of the lesion, as opposed to a maximum innervation of about 47 percent in wild-type animals.

In Nature Neuroscience, principal author Dong Feng Chen and colleagues from Schepens Eye Research Institute, Boston; Goteborg University, Sweden; and Asahikawa Medical College, Japan, report that GFAP/vimentin-null mice also fare better when it comes to integrating neuronal grafts.

First author Reiko Kinouchi and colleagues implanted retinal cells from donor mice into the subretinal space of wild-type or double-KO transgenic animals. The authors then followed the fate of the grafted cells, which expressed enhanced green fluorescent protein as a marker. Kinouchi found little integration of graft tissue into wild-type retina, but about four times as many green neurons in double-knockout retinas, primarily in the ganglion cell layer. Furthermore, most of these cells grew neurites, and confocal images of cells stained with antibodies to neuronal markers indicated that the grafted cells projected axons into the nerve layer.

Together, these results extend previous work from the Goteborg group, which showed that GFAP and vimentin were essential for the glial scar.—Tom Fagan.

References:
Menet V, Prieto M, Privat A, Gimenez y Ribotta M. Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci U S A. 2003 Jul 22 ; 100(15):8999-9004. Abstract

Kinouchi R, Takeda M, Yang L, Wilhelmsson U, Lundkvist A, Pekny M, Chen DF. Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci. 2003 Aug ; 6(8):863-8. Abstract

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References

News Citations

1. Astrocytes May Hold Key to Adult Neurogenesis 22 Nov 2002
2. Got Plaques? Astrocytes to the Rescue! 6 Mar 2003

Other Citations

1. Abstract

Further Reading

Papers

1. Menet V, Prieto M, Privat A, Giménez y Ribotta M. Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8999-9004. PubMed.
2. Kinouchi R, Takeda M, Yang L, Wilhelmsson U, Lundkvist A, Pekny M, Chen DF. Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci. 2003 Aug;6(8):863-8. PubMed.