Remodeling of the Optic Nerve during Metamorphosis in Xenous laevis
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Date
2015-03-24
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Johns Hopkins University
Abstract
The optic nerve of the amphibian Xenopus laevis shortens in length by approximately one-half during its metamorphosis from tadpole to frog. This dramatic shortening event takes place over the course of only a few days at metamorphic climax, when levels of thyroid hormone, the master transcriptional regulator of amphibian metamorphosis, peaks. The shortening of the optic nerve is associated with the remodeling of the retinal ganglion cell axons which make up the nerve. My thesis work focused on how the myelinated axons remodel during optic nerve shortening using primarily electron microscopy based quantitative analyses and reconstructions. Through cell type specific transgenic overexpression of a dominant negative thyroid hormone receptor α construct, the remodeling process was found to involve the distinct but coordinated activities of retinal ganglion cells, oligodendrocytes and astrocytes. Myelin remodeling, in contrast to demyelination, does not involve an immune response. Myelin segments decrease in length proportionally with the optic nerve itself and this shortening involves the production of focal myelin-axon detachments and myelin protrusions from otherwise intact myelin segments. Astrocyte processes selectively remove these local myelin dystrophies from the remodeling segments. This process uses known phagocytic machinery, including the opsonin Mfge8 and the downstream effector involved in cytoskeletal rearrangement, Rac1, as determined by transgenic overexpression of dominant negative constructs in astrocytes. By the end of shortening, one quarter of all myelin in the optic nerve is associated with astrocytes. However, the astrocytes are able to efficiently clear the myelin they internalize within approximately one month after the completion of metamorphosis. These results provide evidence for a new role for astrocytes in the developmental remodeling of myelin segments.
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Keywords
Metamorphosis, Astrocytes