Abstract
BackgroundDespite conserved developmental processes and organization of the vertebrate central nervous system, only some vertebrates including zebrafish can efficiently regenerate neural damage including after spinal cord injury. The mammalian spinal cord shows very limited regeneration and neurogenesis, resulting in permanent life-long functional impairment. Therefore, there is an urgent need to identify the cellular and molecular mechanisms that can drive efficient vertebrate neurogenesis following injury. A key pathway implicated in zebrafish neurogenesis is fibroblast growth factor signaling.MethodsIn the present study we investigated the roles of distinct fibroblast growth factor members and their receptors in facilitating different aspects of neural development and regeneration at different timepoints following spinal cord injury. After spinal cord injury in adults and during larval development, loss and/or gain of Fgf signaling was combined with immunohistochemistry, in situ hybridization and transgenes marking motor neuron populations in in vivo zebrafish and in vitro mammalian PC12 cell culture models.ResultsFgf3 drives neurogenesis of Islet1 expressing motor neuron subtypes and mediate axonogenesis in cMet expressing motor neuron subtypes. We also demonstrate that the role of Fgf members are not necessarily simple recapitulating development. During development Fgf2, Fgf3 and Fgf8 mediate neurogenesis of Islet1 expressing neurons and neuronal sprouting of both, Islet1 and cMet expressing motor neurons. Strikingly in mammalian PC12 cells, all three Fgfs increased cell proliferation, however, only Fgf2 and to some extent Fgf8, but not Fgf3 facilitated neurite outgrowth.ConclusionsThis study demonstrates differential Fgf member roles during neural development and adult regeneration, including in driving neural proliferation and neurite outgrowth of distinct spinal cord neuron populations, suggesting that factors including Fgf type, age of the organism, timing of expression, requirements for different neuronal populations could be tailored to best drive all of the required regenerative processes.
Highlights
Despite conserved developmental processes and organization of the vertebrate central nervous system, only some vertebrates including zebrafish can efficiently regenerate neural damage including after spinal cord injury
Labels radial glia cells across the central nervous system driven by the glial fibrillary acidic protein promoter [44], Tg(Isl1:EGFPrw0) labels secondary motor neurons in the spinal cord [45], Tg(vsx1:GFP) labels interneurons in the spinal cord driven by the visual homeobox 1 promoter [46], Tg(met:GAL4; UAS:EGFP)ed6Tg [47] and Tg(met:mcherry 2A KalTA4)pc24Tg use the C-met promoter to drive reporter expression in primary motorneurons, which represent a distinct population from neurons expressing Islet1 [48]
fibroblast growth factor (Fgf) signalling after spinal cord injury mediates neurogenesis of neurons at the lesion site In order to examine how and in which cells Fgf functions to influence neurogenesis following Spinal cord injury (SCI), we examined the activation of Phosphorylated mitogen activated protein kinase (p-mitogen activated protein kinase (MAPK)) (p44/42), a main downstream effector of the Fgf pathway at the lesion site at 2 weeks post-injury, when we observed highest generation of new neuronal cells in our previous study [2]
Summary
Despite conserved developmental processes and organization of the vertebrate central nervous system, only some vertebrates including zebrafish can efficiently regenerate neural damage including after spinal cord injury. The mammalian spinal cord shows very limited regeneration and neurogenesis, resulting in permanent life-long functional impairment. Spinal cord injury (SCI) triggers very limited regeneration in humans, resulting instead in irreversible damage which can lead to permanent paralysis. Nonmammalian vertebrates, such as fish and urodeles, regenerate damaged nerve cells in their spinal cords efficiently resulting in complete functional recovery even as adults [1,2,3,4]. Among the potential pro-regenerative neural factors, fibroblast growth factor (Fgf ) signalling pathways have been shown influence angiogenesis, mitogenesis, cellular differentiation, cell migration and tissue-injury repair including in the developing and mature brain. Conserved developmental roles have been described in fish [11,12,13]
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