Glial cell line-derived neurotrophic factor alters axon schwann cell units and promotes myelination in unmyelinated nerve fibers - PubMed (original) (raw)

Glial cell line-derived neurotrophic factor alters axon schwann cell units and promotes myelination in unmyelinated nerve fibers

Ahmet Höke et al. J Neurosci. 2003.

Abstract

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the development and maintenance of a subset of dorsal root ganglion sensory neurons. We administered high-dose exogenous recombinant human GDNF (rhGDNF) daily to adult rats to examine its effect on unmyelinated axon-Schwann cell units in intact peripheral nerves. In rhGDNF-treated animals, there was a dramatic proliferation in the Schwann cells of unmyelinated fibers, which resulted in the segregation of many unmyelinated axons into a 1:1 relationship with Schwann cells and myelination of normally unmyelinated small axons. This study demonstrates that the administration of high doses of a growth factor to adult rats can change the phenotype of nerve fibers from unmyelinated to myelinated.

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Figures

Fig. 1.

Fig. 1.

Toluidine blue-stained 1-μm-thick sections of intact sciatic nerves of control vehicle (A) and high-dose rhGDNF-injected (B) rats. In rhGDNF-injected animals, the myelinated fibers were widely separated and the intervening space contained an increased number of unmyelinated Schwann cells. Examples of Schwann cell nuclei are marked by_arrows_ in B. A mitotic figure (arrow) in a Schwann cell in an rhGDNF-injected animal is shown among other Schwann cell nuclei (asterisks) in the inset (original magnification, 1000×).

Fig. 2.

Fig. 2.

Segregation of axon–Schwann cell units and myelination of unmyelinated axons. A, Electron micrograph of an intact sciatic nerve of a control rat at 4 weeks. An example of an unmyelinated fiber is outlined by_arrowheads_ on the basal lamina. This fiber contains 14 axons (examples identified by a; SC, Schwann cell nucleus). B, Electron micrograph of an intact sciatic nerve of a high-dose rhGDNF-treated rat at 4 weeks. Note the marked decrease in the axon–Schwann cell ratio and numerous examples of one or two axons per Schwann cell basal lamina (examples outlined by arrowheads). C, Low-power electron micrograph of the sciatic nerve of an rhGDNF-treated rat shows examples of newly myelinated small axons.D, Some of the small myelinated fibers were still within Remak bundles that also contained unmyelinated axons,Arrowheads point to portions of the basal lamina that are continuous between a myelinated axon and an unmyelinated one (original magnifications, 5000× for A and_B_; 3000× for C; 25,000× for_D_).

Fig. 3.

Fig. 3.

The ratio of unmyelinated axons per Schwann cell basal lamina in intact sciatic nerve in control animals and animals injected with either low-dose (10 mg · kg−1 · d−1) or high-dose (100 mg · kg−1 · d−1) rhGDNF. Each bar represents the average of 150–600 fiber counts combined from different grids. Error bars indicate SEM. *p < 0.005.

Fig. 4.

Fig. 4.

Histograms of the number of axons within a single Schwann cell basal lamina showed a dramatic shift to a higher percentage of Remak bundles, attaining a 1:1 relationship when the rats were treated with rhGDNF for 4 weeks (C) compared with controls (A). The shift was apparent even at 1 week (B). UA, Unmyelinated axon.

Fig. 5.

Fig. 5.

Cumulative line histograms of the diameter of unmyelinated axons in Remak bundles of vehicle-injected control animals and high-dose rhGDNF-injected animals show a shift to larger size.

Fig. 6.

Fig. 6.

Schwann cell and DRG cocultures in the presence of GDNF. A, Sudan black staining shows clear myelination, with the formation of nodes of Ranvier (arrowheads).B, The myelinated nerve fibers express MAG in the paranodal (N) and Schmidt–Lanterman (SL) incisure. C, With the addition of a fluorescent ceramide analog to the culture medium, numerous myelinated fibers could be observed by incorporation of the fluorescent ceramide into the myelin. D, When neutralizing anti-NGF antibody was added to the coculture, myelination appeared to proceed at the normal rate compared with the control culture as assessed by the incorporation of fluorescent ceramide analog.

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