The role of connexin47 in gap junction coupling between astrocytes and oligodendrocytes

In the CNS, gap junctions couple oligodendrocytes and astrocytes (O/A) and adjacent astrocytes (A/A), but not adjacent oligodendrocytes, forming a so-called \u27glial syncytium\u27. A gap junction is an intercellular channel composed of connexins; the composition of these channels depends on the particular connexins expressed by the apposing cells. Genetic experiments of nature and man have shown that the connexins expressed by both oligodendrocytes and astrocytes are required for the proper functioning of myelin and oligodendrocytes, but the underlying physiology of the channels formed by these connexins is unknown. In my thesis work, I have examined the role of connexin47 (Cx47) in the context of the glial syncytium by studying its expression, trafficking, and functional interactions in an in vitro cell model system. First, I have shown that the mutations in GJA12/Cx47 that cause Pelizaeus-Merzbacher-like Disease (PMLD), a devastating leukodystrophy, result in loss-of-function. In order to understand the context of this loss-of-function, I have defined the gap junction channels that most likely form at O/A (Cx47/Cx43 and Cx32/Cx30) and A/A (Cx43/Cx43 and Cx30/Cx30) junctions. Based on these results, I provide evidence that the underlying basis of PMLD is likely to be the loss of Cx47/Cx43 channels at O/A junctions. In addition, Cx32/Cx30 and Cx47/Cx43 channels have distinct functional properties, suggesting that these two channels may have different functions in vivo. Together, this work provides the framework to directly confirm the presence of these channels in vivo and define their functional role in the glial syncytium