Adult zebrafish show a remarkable capacity to regenerate their spinal column after injury, an ability that stands in stark contrast to the limited repair that occurs within the mammalian CNS post-injury. The reasons for this interspecies difference in regenerative capacity remain unclear. Here we demonstrate a novel role for Fgf signaling during glial cell morphogenesis in promoting axonal regeneration after spinal cord injury. Zebrafish glia are induced by Fgf signaling, to form an elongated bipolar morphology that forms a bridge between the two sides of the resected spinal cord, over which regenerating axons actively migrate. Loss of Fgf function inhibits formation of this "glial bridge" and prevents axon regeneration. Despite the poor potential for mammalian axonal regeneration, primate astrocytes activated by Fgf signaling adopt a similar morphology to that induced in zebrafish glia. This suggests that differential Fgf regulation, rather than intrinsic cell differences, underlie the distinct responses of mammalian and zebrafish glia to injury.

Spinal cord injury usually results in permanent paralysis because of lack of regrowth of damaged neurons. Here we demonstrate that adult mice lacking EphA4 (Ϫ/Ϫ), a molecule essential for correct guidance of spinal cord axons during development, exhibit axonal regeneration and functional recovery after spinal cord hemisection. Anterograde and retrograde tracing showed that axons from multiple pathways, including corticospinal and rubrospinal tracts, crossed the lesion site. EphA4Ϫ/Ϫ mice recovered stride length, the ability to walk on and climb a grid, and the ability to grasp with the affected hindpaw within 1-3 months of injury. EphA4 expression was upregulated on astrocytes at the lesion site in wild-type mice, whereas astrocytic gliosis and the glial scar were greatly reduced in lesioned EphA4Ϫ/Ϫ spinal cords. EphA4Ϫ/Ϫ astrocytes failed to respond to the inflammatory cytokines, interferon-␥ or leukemia inhibitory factor, in vitro. Neurons grown on wild-type astrocytes extended shorter neurites than on EphA4Ϫ/Ϫ astrocytes, but longer neurites when the astrocyte EphA4 was blocked by monomeric EphrinA5-Fc. Thus, EphA4 regulates two important features of spinal cord injury, axonal inhibition, and astrocytic gliosis.

No abstract

Considerable debate continues regarding thalamic inputs to the middle temporal area (MT) of the visual cortex that bypass the primary visual cortex (V1) and the role they might have in the residual visual capability following a lesion of V1. Two specific retinothalamic projections to area MT have been speculated to relay through the medial portion of the inferior pulvinar nucleus (PIm) and the koniocellular layers of the dorsal lateral geniculate nucleus (LGN). Although a number of studies have demonstrated retinal inputs to regions of the thalamus where relays to area MT have been observed, the relationship between the retinal terminals and area MT relay cells has not been established. Here we examined direct retino-recipient regions of the marmoset monkey (Callithrix jacchus) pulvinar nucleus and the LGN following binocular injections of anterograde tracer, as well as area MT relay cells in these nuclei by injection of retrograde tracer into area MT. Retinal afferents were shown to synapse with area MT relay cells as demonstrated by colocalization with the presynaptic vesicle membrane protein synaptophysin. We also established the presence of direct synapes of retinal afferents on area MT relay cells within the PIm, as well as the koniocellular K1 and K3 layers of the LGN, thereby corroborating the existence of two disynaptic pathways from the retina to area MT that bypass V1.