Neuronal Regeneration from Ependymo-Radial Glial Cells: Cook, Little Pot, Cook!
2015; Elsevier BV; Volume: 32; Issue: 4 Linguagem: Inglês
10.1016/j.devcel.2015.01.001
ISSN1878-1551
AutoresCatherina G. Becker, Thomas Becker,
Tópico(s)MicroRNA in disease regulation
ResumoAdult fish and salamanders regenerate specific neurons as well as entire CNS areas after injury. Recent studies shed light on how these anamniotes activate progenitor cells, generate the required cell types, and functionally integrate these into a complex environment. Some developmental signals and mechanisms are recapitulated during neuronal regeneration, whereas others are unique to the regeneration process. The use of genetic techniques, such as cell ablation and lineage-tracing, in combination with cell-type-specific expression profiling reveal factors that initiate, fine-tune, and terminate the regenerative response in anamniotes, with a view to translating findings to non-regenerating species. Adult fish and salamanders regenerate specific neurons as well as entire CNS areas after injury. Recent studies shed light on how these anamniotes activate progenitor cells, generate the required cell types, and functionally integrate these into a complex environment. Some developmental signals and mechanisms are recapitulated during neuronal regeneration, whereas others are unique to the regeneration process. The use of genetic techniques, such as cell ablation and lineage-tracing, in combination with cell-type-specific expression profiling reveal factors that initiate, fine-tune, and terminate the regenerative response in anamniotes, with a view to translating findings to non-regenerating species. So the child went into the forest, and there an aged woman met her who was aware of her sorrow, and presented her with a little pot, which when she said, "Cook, little pot, cook," would cook good, sweet porridge, and when she said, "Stop, little pot," it ceased to cook.—Jacob and Wilhelm Grimm (Kinder- und Hausmärchen) The regenerative capacity of the human CNS is lamentably low (Gage and Temple, 2013Gage F.H. Temple S. Neural stem cells: generating and regenerating the brain.Neuron. 2013; 80: 588-601Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Specific neuronal cell types that are lost in degenerative diseases, such as dopaminergic neurons in Parkinson's disease (van den Berge et al., 2013van den Berge S.A. van Strien M.E. Hol E.M. Resident adult neural stem cells in Parkinson's disease—the brain's own repair system?.Eur. J. Pharmacol. 2013; 719: 117-127Crossref PubMed Scopus (3) Google Scholar) or motor neurons in motor neuron disease (Winner et al., 2014Winner B. Marchetto M.C. Winkler J. Gage F.H. Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease.Hum. Mol. Genet. 2014; 23: R27-R34Crossref PubMed Scopus (3) Google Scholar) are never replaced. The same holds true for extensive neuron loss in stroke (Merson and Bourne, 2014Merson T.D. Bourne J.A. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies.Int. J. Biochem. Cell Biol. 2014; 56C: 4-19Crossref Scopus (2) Google Scholar) or around a spinal cord injury (David et al., 2012David S. Zarruk J.G. Ghasemlou N. Inflammatory pathways in spinal cord injury.Int. Rev. Neurobiol. 2012; 106: 127-152Crossref PubMed Scopus (11) Google Scholar). What if we had the means to replenish neurons at will and switch off regeneration when the task is done, in the same way the pot in the Grimm's fairy tale provides an unending stream of sweet porridge (Grimm and Grimm, 1812Grimm J. Grimm W. Der süße Brei (Sweet Porridge); KMH 103.in: Grimm J. Grimm W. Kinder- und Hausmärchen. Realschulbuchhandlung, Berlin1812Google Scholar)? Anamniote vertebrates, particularly salamanders and fishes, seem to possess such a pot, as they regenerate entire tissues in the CNS, such as retina, brain, and spinal cord (Figure 1; Table 1). While these phenomena have been known for some time (Kirsche, 1950Kirsche W. Die regenerativen Vorgänge am Rückenmark erwachsener Teleostier nach operativer Kontinuitätstrennung.Z. Mikrosk. Anat. Forsch. 1950; 56: 190-265Google Scholar and citations therein), we are now in a position to gain a deeper understanding of the cellular and molecular signaling pathways involved (recently reviewed in Berg et al., 2013Berg D.A. Belnoue L. Song H. Simon A. Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain.Development. 2013; 140: 2548-2561Crossref PubMed Scopus (17) Google Scholar, Gemberling et al., 2013Gemberling M. Bailey T.J. Hyde D.R. Poss K.D. The zebrafish as a model for complex tissue regeneration.Trends Genet. 2013; 29: 611-620Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, Goldman, 2014Goldman D. Müller glial cell reprogramming and retina regeneration.Nat. Rev. Neurosci. 2014; 15: 431-442Crossref PubMed Scopus (8) Google Scholar, Gorsuch and Hyde, 2014Gorsuch R.A. Hyde D.R. Regulation of Müller glial dependent neuronal regeneration in the damaged adult zebrafish retina.Exp. Eye Res. 2014; 123: 131-140Crossref PubMed Scopus (7) Google Scholar, Lenkowski and Raymond, 2014Lenkowski J.R. Raymond P.A. Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish.Prog. Retin. Eye Res. 2014; 40: 94-123Crossref PubMed Scopus (9) Google Scholar). Elucidating how this regeneration is accomplished at the cellular and molecular level may answer fundamental questions as to how stem/progenitor cells are directed to make new neurons, how this process is initiated and promoted, but also limited in space and time. Moreover, it is important to understand how regeneration of appropriate cell types and their integration into an existing, complex CNS environment is achieved.Table 1Regeneration-Associated Cellular Events and Molecular Signals for Different Experimental ModelsModelRegenerated Neuron TypesNetwork Integration/Return of FunctionInitiating/Promoting FactorsStopping/Attenuating FactorsRegeneration-Specific?Amphibian tail ablationentire spinal cordnormal movement restoredFgf, RA, Bmp, Notch signaling–sox2 in ERGs only required for regenerationSalamander dopaminergic cell ablationdopaminergic neuronsaxon regrowth, amphetamine-induced locomotion restoredreduced dopamine levels, Shh signalingrestored dopamine levels–Knife fish tail ablationspecialized electric motor neuronsreturn of electrosensation–––Zebrafish telencephalon stab lesionparvalbuminergic neuronsSV2+ puncta on neurons, commissural axon growthmicroglia-derived factors (leukotriene C4 and Cxcr signaling), Notch signalingERG proliferation attenuated by id1regeneration-specific role of gata3Zebrafish spinal cord transectionmotor neurons, serotonergic neurons, V2 interneurons, Pax2+ interneuronsSV2+ puncta on motor neurons, growth of motor axons into muscle peripherymicroglia (?), Shh, Fgf, RA (?), dopamineNotch signalingregeneration-specific expression of Notch ligands(?) denotes not yet functionally tested. Open table in a new tab (?) denotes not yet functionally tested. In this review, we give an overview of the capacity of the CNS of amphibians and fishes to regenerate neurons. We summarize recent exciting advances showing that in the brain and spinal cord, ependymo-radial glia progenitor cells are major contributors to the repair process. These cells are heterogeneous and regenerate different functional neurons. Neurogenesis is initiated, promoted, and controlled by regeneration-specific signals; e.g., from the immune system, and by developmental signals that are re-deployed in regeneration. We also discuss similarities to the lesion response in mammals. Anamniotes regenerate entire tissues in the CNS, such as the retina or the caudal spinal cord during tail regeneration, termed "epimorphic" regeneration (Fei et al., 2014Fei J.F. Schuez M. Tazaki A. Taniguchi Y. Roensch K. Tanaka E.M. CRISPR-mediated genomic deletion of Sox2 in the axolotl shows a requirement in spinal cord neural stem cell amplification during tail regeneration.Stem Cell Reports. 2014; 3: 444-459Abstract Full Text Full Text PDF Scopus (2) Google Scholar). Another form of neuronal regeneration occurs in the tissue surrounding an injury, such as stab (Kyritsis et al., 2012Kyritsis N. Kizil C. Zocher S. Kroehne V. Kaslin J. Freudenreich D. Iltzsche A. Brand M. Acute inflammation initiates the regenerative response in the adult zebrafish brain.Science. 2012; 338: 1353-1356Crossref PubMed Scopus (63) Google Scholar, März et al., 2011März M. Schmidt R. Rastegar S. Strähle U. Regenerative response following stab injury in the adult zebrafish telencephalon.Dev. Dyn. 2011; 240: 2221-2231Crossref PubMed Scopus (23) Google Scholar) or toxic lesions (Skaggs et al., 2014Skaggs K. Goldman D. Parent J.M. Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long-distance neuronal integration.Glia. 2014; 62: 2061-2079Crossref PubMed Google Scholar). Here, new neurons are integrated into an existing tissue. We call this "interstitial" regeneration for the purpose of this review. A third type of regeneration is observed after specific ablation of individual cell types; e.g., using specific toxins to ablate dopaminergic neurons (Figure 1) (Berg et al., 2010Berg D.A. Kirkham M. Beljajeva A. Knapp D. Habermann B. Ryge J. Tanaka E.M. Simon A. Efficient regeneration by activation of neurogenesis in homeostatically quiescent regions of the adult vertebrate brain.Development. 2010; 137: 4127-4134Crossref PubMed Scopus (29) Google Scholar). Interstitial regeneration would be needed for repair of secondary neuron loss around a stroke or spinal injury, and cell type specific regeneration would be needed in neurodegenerative diseases; e.g., for dopaminergic neurons in Parkinson's disease or motor neurons in motor neuron diseases (David et al., 2012David S. Zarruk J.G. Ghasemlou N. Inflammatory pathways in spinal cord injury.Int. Rev. Neurobiol. 2012; 106: 127-152Crossref PubMed Scopus (11) Google Scholar, Merson and Bourne, 2014Merson T.D. Bourne J.A. Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies.Int. J. Biochem. Cell Biol. 2014; 56C: 4-19Crossref Scopus (2) Google Scholar, van den Berge et al., 2013van den Berge S.A. van Strien M.E. Hol E.M. Resident adult neural stem cells in Parkinson's disease—the brain's own repair system?.Eur. J. Pharmacol. 2013; 719: 117-127Crossref PubMed Scopus (3) Google Scholar, Winner et al., 2014Winner B. Marchetto M.C. Winkler J. Gage F.H. Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease.Hum. Mol. Genet. 2014; 23: R27-R34Crossref PubMed Scopus (3) Google Scholar). This makes it important to understand how anamniotes accomplish these types of repair. Salamanders (urodeles) are the only tetrapod models of successful regeneration of the adult CNS. A prominent model species is the axolotl (Ambystoma mexicanum), which is neotenic, that is it retains larval features as an adult, such as gills and larval skin histology, but is fully capable of reproduction. Metamorphosis can be induced by injection of thyroxine, which, however, has little influence on their regenerative capacity (Ehrlich and Mark, 1977Ehrlich D. Mark R.F. Fiber counts of regenerating peripheral nerves in axolotls and the effect of metamorphosis.J. Comp. Neurol. 1977; 174: 307-316Crossref PubMed Google Scholar, Voss et al., 2013Voss G.J. Kump D.K. Walker J.A. Voss S.R. 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In electrosensory knife fishes, epimorphic regeneration of the caudal spinal cord, including the specialized neurons of the electric organ at the tip of their tails, has been observed (Waxman and Anderson, 1985Waxman S.G. Anderson M.J. Generation of electromotor neurons in Sternarchus albifrons: differences between normally growing and regenerating spinal cord.Dev. Biol. 1985; 112: 338-344Crossref PubMed Scopus (19) Google Scholar). Stab lesions to the cerebellum lead to regeneration of granule cells in a knife fish (Zupanc and Ott, 1999Zupanc G.K. Ott R. Cell proliferation after lesions in the cerebellum of adult teleost fish: time course, origin, and type of new cells produced.Exp. Neurol. 1999; 160: 78-87Crossref PubMed Scopus (68) Google Scholar), and in the goldfish, serotonergic neurons regenerate after a spinal lesion (Takeda et al., 2008Takeda A. Nakano M. Goris R.C. Funakoshi K. Adult neurogenesis with 5-HT expression in lesioned goldfish spinal cord.Neuroscience. 2008; 151: 1132-1141Crossref PubMed Scopus (21) Google Scholar). Recently, the 2.5–4 cm long zebrafish has entered the stage as a new model for studying CNS regeneration. Genetic tools that have been applied to studies of zebrafish development are now being deployed to facilitate studies of regeneration in adults (Gemberling et al., 2013Gemberling M. Bailey T.J. Hyde D.R. Poss K.D. The zebrafish as a model for complex tissue regeneration.Trends Genet. 2013; 29: 611-620Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, Grandel and Brand, 2013Grandel H. Brand M. Comparative aspects of adult neural stem cell activity in vertebrates.Dev. Genes Evol. 2013; 223: 131-147Crossref PubMed Scopus (31) Google Scholar). Unlike mammals (Cregg et al., 2014Cregg J.M. DePaul M.A. Filous A.R. Lang B.T. Tran A. Silver J. Functional regeneration beyond the glial scar.Exp. 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Retinal regeneration in adult zebrafish requires regulation of TGFβ signaling.Glia. 2013; 61: 1687-1697Crossref PubMed Scopus (9) Google Scholar, März et al., 2011März M. Schmidt R. Rastegar S. Strähle U. Regenerative response following stab injury in the adult zebrafish telencephalon.Dev. Dyn. 2011; 240: 2221-2231Crossref PubMed Scopus (23) Google Scholar, Reimer et al., 2008Reimer M.M. Sörensen I. Kuscha V. Frank R.E. Liu C. Becker C.G. Becker T. Motor neuron regeneration in adult zebrafish.J. Neurosci. 2008; 28: 8510-8516Crossref PubMed Scopus (76) Google Scholar). For example, the transected spinal cord of adult zebrafish fuses again, likely mediated by dedifferentiating glial cells (Goldshmit et al., 2012Goldshmit Y. Sztal T.E. Jusuf P.R. Hall T.E. Nguyen-Chi M. Currie P.D. Fgf-dependent glial cell bridges facilitate spinal cord regeneration in zebrafish.J. Neurosci. 2012; 32: 7477-7492Crossref PubMed Scopus (40) Google Scholar). However, the lesion site remains as a narrow tissue bridge, comprised mostly of regenerated descending axons and glial cells, which make contact with the caudal spinal cord (Reimer et al., 2008Reimer M.M. Sörensen I. Kuscha V. Frank R.E. Liu C. Becker C.G. Becker T. Motor neuron regeneration in adult zebrafish.J. Neurosci. 2008; 28: 8510-8516Crossref PubMed Scopus (76) Google Scholar). Hence, at the tissue level, the zebrafish CNS is repaired after a lesion. Different types of neurons regenerate in the zebrafish CNS environment. For example, regeneration of all major retinal cell types is observed after cytotoxic, mechanical, and light lesion of the retina (Goldman, 2014Goldman D. Müller glial cell reprogramming and retina regeneration.Nat. Rev. Neurosci. 2014; 15: 431-442Crossref PubMed Scopus (8) Google Scholar) and parvalbuminergic and other neurons regenerate after stab or neurotoxic lesions of the telencephalon (Kroehne et al., 2011Kroehne V. Freudenreich D. Hans S. Kaslin J. 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These cells span the entire width of the brain (Berg et al., 2011Berg D.A. Kirkham M. Wang H. Frisén J. Simon A. Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons.Cell Stem Cell. 2011; 8: 426-433Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, Dirian et al., 2014Dirian L. Galant S. Coolen M. Chen W. Bedu S. Houart C. Bally-Cuif L. Foucher I. Spatial regionalization and heterochrony in the formation of adult pallial neural stem cells.Dev. Cell. 2014; 30: 123-136Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar) or spinal cord (Reimer et al., 2008Reimer M.M. Sörensen I. Kuscha V. Frank R.E. Liu C. Becker C.G. Becker T. Motor neuron regeneration in adult zebrafish.J. Neurosci. 2008; 28: 8510-8516Crossref PubMed Scopus (76) Google Scholar, Reimer et al., 2009Reimer M.M. Kuscha V. Wyatt C. Sörensen I. Frank R.E. Knüwer M. Becker T. Becker C.G. 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However, contrary to radial glia, these cells also have clear ependymal features; e.g., in the zebrafish spinal cord they contribute to the ependyma and may possess motile cilia (L. Saude, personal communication; see Becker and Diez del Corral, 2015Becker C.G. Diez del Corral R. Neural development and regeneration: it's all in your spinal cord.Development. 2015; (in press)https://doi.org/10.1242/dev.121053Crossref PubMed Google Scholar). We therefore designated these cells in adult anamniotes "ependymo-radial glia (ERG)" (Reimer et al., 2008Reimer M.M. Sörensen I. Kuscha V. Frank R.E. Liu C. Becker C.G. Becker T. Motor neuron regeneration in adult zebrafish.J. Neurosci. 2008; 28: 8510-8516Crossref PubMed Scopus (76) Google Scholar). ERGs have also been described as "radial glia" (Fei et al., 2014Fei J.F. Schuez M. Tazaki A. Taniguchi Y. Roensch K. Tanaka E.M. CRISPR-mediated genomic deletion of Sox2 in the axolotl shows a requirement in spinal cord neural stem cell amplification during tail regeneration.Stem Cell Reports. 2014; 3: 444-459Abstract Full Text Full Text PDF Scopus (2) Google Scholar, Kroehne et al., 2011Kroehne V. Freudenreich D. Hans S. Kaslin J. Brand M. Regeneration of the adult zebrafish brain from neurogenic radial glia-type progenitors.Development. 2011; 138: 4831-4841Crossref PubMed Scopus (69) Google Scholar), "tanycyte" (Reichenbach and Wolburg, 2013Reichenbach A. Wolburg W. Astrocytes and ependymal glia.in: Kettenmann H. Ransom B.R. Neuroglia. Oxford University Press, Oxford2013: 35-49Google Scholar), or "ependymoglia" (Kirkham et al., 2014Kirkham M. Hameed L.S. Berg D.A. Wang H. Simon A. Progenitor cell dynamics in the Newt Telencephalon during homeostasis and neuronal regeneration.Stem Cell Reports. 2014; 2: 507-519Abstract Full Text Full Text PDF Scopus (4) Google Scholar).Figure 3Distinct Domains of ERGs in the Adult Zebrafish Spinal Cord Give Rise to Different Types of Neurons after a LesionShow full captionIn a spinal cross section, olig2:Ds-Red expressing ERGs are depicted by arrows (non-ERGs are also labeled) and schematically depicted within their specific domain. Domains are defined by expression of combinations of transcription factors in ERGs. After a lesion, these give rise to the types of neurons indicated. olig2:Ds-Red expressing ERGs are distinct from gfap:GFP expressing ERGs.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In a spinal cross section, olig2:Ds-Red expressing ERGs are depicted by arrows (non-ERGs are also labeled) and schematically depicted within their specific domain. Domains are defined by expression of combinations of transcription factors in ERGs. After a lesion, these give rise to the types of neurons indicated. olig2:Ds-Red expressing ERGs are distinct from gfap:GFP expressing ERGs. Are ERGs stem cells; i.e., do they self-renew and give rise to different neural cell types? Given that there are constitutively active neurogenic zones in the unlesioned CNS of anamniotes, and the fact that upon proliferation and regeneration of CNS tissue ERGs are not consumed, it is possible that
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