Gibbs KM et al. (2011), Metamorphosis and the regenerative capacity of ...

XB-ART-42215

Eur J Neurosci 2011 Jan 01;331:9-25. doi: 10.1111/j.1460-9568.2010.07477.x.

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Metamorphosis and the regenerative capacity of spinal cord axons in Xenopus laevis.

Gibbs KM , Chittur SV , Szaro BG .

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Throughout the vertebrate subphylum, the regenerative potential of central nervous system axons is greatest in embryonic stages and declines as development progresses. For example, Xenopus laevis can functionally recover from complete transection of the spinal cord as a tadpole but is unable to do so after metamorphosing into a frog. Neurons of the reticular formation and raphe nucleus are among those that regenerate axons most reliably in tadpole and that lose this ability after metamorphosis. To identify molecular factors associated with the success and failure of spinal cord axon regeneration, we pharmacologically manipulated thyroid hormone (TH) levels using methimazole or triiodothyronine, to either keep tadpoles in a permanently larval state or induce precocious metamorphosis, respectively. Following complete spinal cord transection, serotonergic axons crossed the lesion site and tadpole swimming ability was restored when metamorphosis was inhibited, but these events failed to occur when metamorphosis was prematurely induced. Thus, the metamorphic events controlled by TH led directly to the loss of regenerative potential. Microarray analysis identified changes in hindbrain gene expression that accompanied regeneration-permissive and -inhibitory conditions, including many genes in the permissive condition that have been previously associated with axon outgrowth and neuroprotection. These data demonstrate that changes in gene expression occur within regenerating neurons in response to axotomy under regeneration-permissive conditions in which normal development has been suspended, and they identify candidate genes for future studies of how central nervous system axons can successfully regenerate in some vertebrates.

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Species referenced: Xenopus laevis
Genes referenced: fabp7 myh3 nefm

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Fig. 4. Serotonergic axons crossing the lesion site in a methimazole-treated tadpole at 5 weeks. Parasagittal cryosections were immunostained for NF-M (green) to label axons, and for serotonin (red) to identify axons within the descending tracts originating from reticular and raphe nuclei (see text). (A and B) A low-power view [20 0.75 NA; one optical section 1.3, 1.3, 2.1 lm (x, y,z)] of a parasagittal section through the spinal cord of an unoperated animal to illustrate the presence of serotonergic axons within the descending tract. NF-M (A, green) and serotonin (B, red) immunostraining are shown separately. (C) A low-power view [20 0.75 NA; one optical section 0.9, 0.9, 2.1 lm (x, y,z)] of descending axons crossing the lesion site (boxed region). NF-M (green) and serotonin (red) immunostaining are superimposed. (D) View of the boxed region in C at higher magniﬁcation [63 1.4 NA; one optical section 0.14, 0.14, 0.3 lm (x, y,z)], with NF-M (green) and serotonin (red) immunostaining viewed separately in D and E, respectively, and superimposed in F. Arrows point to examples of axons double-labeled for NF-M and serotonin. Dorsal is up, and rostral is to the left. Scale bar in A also applies to B, and that in D also applies to E and F.

Fig. 5. Regenerating axons follow radial glia across the lesion site in untreated (A'') and methimazole-treated (B''), but not in T3-treated (C'') tadpoles. Axons and radial glia are labeled by immunostaining for NF-M (green, A) and BLBP (red, A''), respectively. Channels are shown separately in A and A'' and are merged in A''''. Each image represents a single optical section [A, B 20 0.75 NA; 0.3, 0.3, 2.1 lm (x, y, z). C 20 0 ⁄ 75 NA; 0.5, 0.5, 2.1 lm (x, y, z)] of a parasagittal anatomical section; rostral is to the left. The lesion site is indicated by a horizontal bracket.