Altered gene expression in Schwann cells of connexin32 knockout animals

The discovery that the dominant X-linked form of Charcot-Marie-Tooth diseas e (CMTX), a genetic disease of the peripheral nervous system (PNS), is asso ciated with mutations in connexin32 (Cx32) has brought attention to the imp ortance of connexins in glial cell biology. To gain further insight into th e consequences of Cx32 deficiency, we have undertaken a detailed characteri zation of the gene expression profile of Schwann cells isolated from the sc iatic nerve of wild-type and Cx32-null mice. Schwann cells exhibit two dist inct phenotypes, myelinating and nonmyelinating, which are defined by their different morphology with respect to axons and by their unique profile of gene expression. Our findings show that, regardless of the mouse genotype, cultured Schwann cells express similar levels of messages for a number of c onnexins and for genes characteristic of both the myelinating and the nonmy elinating phenotypes. Furthermore, we have identified Cx36, a member of the gamma subclass of connexins, which are preferentially expressed in neurona l cells of mouse brain and retina, as an additional connexin present in Sch wann cells. Mice lacking Cx32, however, exhibited a marked up-regulation of glial fibrillary acidic protein (GFAP), a cytoskeletal protein usually syn thesized only by nonmyelinating Schwann cells. This observation was extende d to the PNS in vivo and did not reflect a general perturbation of the expr ession of other nonmyelinating Schwann cell genes. These findings demonstra te that the absence of Cx32 results in a distinct pattern of gene dysregula tion in Schwann cells and that Schwann cell homeostasis is critically depen dent on the correct expression of Cx32 and not just any connexin. Identifyi ng the relationship between increased GFAP expression and the absence of Cx 32 could lead to the definition of specific roles for Cx32 in the control o f myelin homeostasis and in the development of CMTX. (C) 2001 Wiley-Liss, I nc.