Intercellular channels permit the direct exchange of ions and small molecules between adjacent cells. These channels are formed from connexins, a family of at least 13 genes. Mutations in connexin (Cx) genes have been associated with neurodegenerative diseases, deafness, cataracts and cardiovascular abnormalities. The goals of this proposal are to identify the cell or tissue functions that require intercellular communication via connexins and to understand why such diversity among connexins is required for these effects. Toward this end, we have generated lines of mice lacking different connexin genes.
Mutations in the gene encoding connexin32 (Cx32) cause a demyelinating peripheral neuropathy known as Charcot-Marie-Tooth disease (CMTX). Consistent with this finding, Schwann cells express Cx32 and co-regulate its expression with that of other myelin-related gene products. Oligodendrocytes were found to similarly regulate Cx32 expression, and yet central nervous system abnormalities are rare in CMTX patients. One explanation that might account for this finding would be the redundant expression of other connexin genes in myelinating glia. In this regard, we have identified two novel connexins, Cx29 and Cx47. All three connexins are found in both oligodendrocytes and Schwann cells. Cx29 and Cx32, however, are present in non-overlapping subsets of spinal cord oligodendrocytes. Moreover, while both connexins are present in Schwann cells, their subcellular distributions are strikingly different. Gene disruption of either Cx32 or Cx47 results in no overt functional deficits, but mice deficient in both gene products develop severe central demyelination and die during the 6th postnatal week of life. We have also shown that this loss of central nervous system myelin is activity-dependent. Increasing the rate of retinal ganglion cell firing greatly accelerates the onset of the pathology while suppression of firing has the opposite effect. These findings are consistent with a model in which connexin channels provide part of a pathway for the removal of potassium, ions released from the axon during spiking. Nevertheless, the precise function of connexins in coordinating or regulating myelin formation remain unclear. Furthermore, connexin function in Schwann cells, which do not communicate with adjacent cells via gap junctions, is likely to be very different from that in oligodendrocytes, which are extensively coupled to astrocytes. Currently, we are defining the separate and interacting roles of connexins in myelination using a combination of immunocytochemistry, targeted gene ablation and functional analysis of connexin channel activity.
