Altered Connexin Expression after Peripheral Nerve Injury

Chandross, Karen J.; Kessler, John A.; Cohen, Rick I.; Simbürger, Eva; Spray, David C.; Bieri, Phyllis; Dermietzel, Rolf

doi:10.1006/mcne.1996.0036

Cited by 96 publications

(81 citation statements)

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“…Myelinating Schwann cells express Cx32, and its expression appears to be regulated at the level of transcription in concert with many myelin-related genes (Scherer et al, 1995;Chandross et al, 1996;Söhl et al, 1996). Cx32 is prominently localized in noncompact myelin and may help form a radial pathway that mediates the diffusion of small molecules and ions directly across the layers of the myelin sheath (Balice-Gordon et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…In wild-type mice, Cx32 was mainly localized to incisures and paranodes (Fig. 4 A), with lesser amounts in the inner and outer mesaxons (Bergoffen et al, 1993;Scherer et al, 1995;Chandross et al, 1996;Balice-Gordon et al, 1998;Meier et al, 2004). No Cx32 immunoreactivity was seen in TG Ϫ cx32…”

Section: Tg ؉ Myelinating Schwann Cells But Not Oligodendrocytes Exprmentioning

confidence: 97%

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Transgenic Expression of HumanConnexin32in Myelinating Schwann Cells Prevents Demyelination inConnexin32-Null Mice

Scherer¹,

Xu²,

Messing³

et al. 2005

J. Neurosci.

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Mutations in Gap Junction ␤1 (GJB1), the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We investigated the possibility that the expression of mutant Cx32 in other cells besides myelinating Schwann cells contributes to the development of demyelination. Human Cx32 was expressed in transgenic mice using a rat myelin protein zero (Mpz) promoter, which is exclusively expressed by myelinating Schwann cells. Male mice expressing the human transgene were crossed with female Gjb1/cx32-null mice; the resulting male offspring were all cx32-null (on the X chromosome), and one-half were transgene positive. In these transgenic mice, all of the Cx32 was derived from the expression of the transgene and was found in the sciatic nerve but not in the spinal cord or the liver. Furthermore, the Cx32 protein was properly localized (within incisures and paranodes) in myelinating Schwann cells. Finally, the expression of human Cx32 protein "rescued" the phenotype of cx32-null mice, because the transgenic mice have significantly fewer demyelinated or remyelinated axons than their nontransgenic littermates. These results indicate that the loss of Schwann-cell-autonomous expression of Cx32 is sufficient to account for demyelination in CMT1X.

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Section: Discussionmentioning

confidence: 99%

Section: Tg ؉ Myelinating Schwann Cells But Not Oligodendrocytes Exprmentioning

confidence: 97%

Transgenic Expression of HumanConnexin32in Myelinating Schwann Cells Prevents Demyelination inConnexin32-Null Mice

Scherer¹,

Xu²,

Messing³

et al. 2005

J. Neurosci.

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“…This view has been reinforced by the apparent absence of non-ocular abnormalities in the Cx46 and Cx50 knock-out mice (3,4). However, several studies have documented the expression of Cx46 and Cx50 in tissues other than the lens, including heart (15-18), kidney (16,57), alveolar epithelial cells (58), osteoblastic cells (59), retina (60,61), and degenerating Schwann cells (62). In this study we demonstrate that in addition to the lens, Cx48.5 is expressed in the embryonic and adult heart, in the early otic vesicles, and adult testes.…”

Section: Discussionmentioning

confidence: 99%

Connexin 48.5 Is Required for Normal Cardiovascular Function and Lens Development in Zebrafish Embryos

Cheng

Shakespeare

Mui

et al. 2004

Journal of Biological Chemistry

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Gap junctions are composed of connexin (Cx) proteins and mediate intercellular communication required for many developmental and physiological processes. Here we describe the isolation and characterization of Cx48.5, a zebrafish connexin with the highest sequence identity to mammalian Cx46. Expression analysis showed that Cx48.5 is expressed in the adult and embryonic lens and heart, adult testis, and transiently in the embryonic otic vesicles. Injection of Cx48.5 cRNA into Xenopus oocytes elicited intercellular electrical coupling with voltage sensitivity similar to mammalian Cx46. In single oocytes, Cx48.5 also induced large outward currents on depolarization, consistent with gap-junctional hemichannels. Disruption of Cx48.5 expression in embryos with antisense morpholino oligos (morpholinos) revealed that Cx48.5 has an essential role in the maintenance of lens homeostasis. The morpholino-treated embryos also developed small lenses and eyes as well as severe cardiovascular abnormalities.Gap junctions are clusters of intercellular channels that allow the propagation of small metabolites, signaling molecules, and electrical impulses between adjacent cells. The protein units that make up the gap junction channels in vertebrates are called connexins and are coded for by a multigene family with 20 or more members in mammals (1). Gap junctions play vital roles in the functions of virtually all organs, including the lens and the heart. The evidence to date suggests that distinct sets of connexins may play a role in the development and function of organs like the lens and the heart. Three connexins are expressed in the mammalian lens. Connexin 43 is expressed in the undifferentiated lens epithelium, whereas Cx46 1 and Cx50 are typically considered lens-specific and are predominantly expressed in the lens fiber cells (for review, see Ref.2). Both Cx46 and Cx50 knock-out mice developed cataracts (3-5), and the Cx50 knock-out mice also developed small lenses and small eyes.Four connexins are abundantly expressed in the mammalian heart: Cx43, Cx40, Cx45, and Cx37. Connexin 43 is expressed in the atrial and ventricular working myocardium, Cx40 is found in the atrial working myocardium and the conducting bundle branches and Purkinje fibers, whereas Cx45 is restricted to the atrioventricular conduction system, and Cx37 is restricted to endothelial and endocardial cells (for reviews, see Refs. 6 -8). Mouse knock-out experiments have demonstrated that Cx43, Cx40, and Cx45 are all essential for cardiac development and function. For instance, connexin 43 knock-out mice died neonatally from pulmonary outflow tract obstruction (9). Connexin 40-deficient mice on the other hand exhibited slowed cardiac conduction and a partial atrioventricular block (10, 11). Last, Cx45 knock-out mice died by embryonic day 10 displaying the effects of a conduction block, endocardial cushion defects, and abnormalities of vascular development (12, 13). The Cx37 knock-out mice had no apparent cardiovascular abnormalities (14). Although the expression a...

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“…In wild-type mice, Cx32 is mainly localized to incisures and paranodes (Bergoffen et al, 1993;Scherer et al, 1995;Chandross et al, 1996;Meier et al, 2004). To determine the localization of transgenic/mutant Cx32, we immunostained unfixed teased fibers from adult TG ϩ mice in a wild-type background, from 10 different lines (six lines C280G and four lines S281x).…”

Section: The Localization Of C280g and S281x Mutants In A Wild-type Bmentioning

confidence: 99%

Prenylation-Defective Human Connexin32 Mutants Are Normally Localized and Function Equivalently to Wild-Type Connexin32 in Myelinating Schwann Cells

Huang

Sirkowski²,

Stickney³

et al. 2005

J. Neurosci.

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Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-MarieTooth disease, an inherited demyelinating neuropathy. The C terminus of human Cx32 contains a putative prenylation motif that is conserved in Cx32 orthologs. Using [ 3 H]mevalonolactone ([ 3 H]MVA) incorporation, we demonstrated that wild-type human connexin32 can be prenylated in COS7 cells, in contrast to disease-associated mutations that are predicted to disrupt the prenylation motif. We generated transgenic mice that express these mutants in myelinating Schwann cells. Male mice expressing a transgene were crossed with female Gjb1-null mice; the male offspring were all Gjb1-null, and one-half were transgene positive; in these mice, all Cx32 was derived from expression of the transgene. The mutant human protein was properly localized in myelinating Schwann cells in multiple transgenic lines and did not alter the localization of other components of paranodes and incisures. Finally, both the C280G and the S281x mutants appeared to "rescue" the phenotype of Gjb1-null mice, because transgene-positive male mice had significantly fewer abnormally myelinated axons than did their transgene-negative male littermates. These results indicate that Cx32 is prenylated, but that prenylation is not required for proper trafficking of Cx32 and perhaps not even for certain aspects of its function, in myelinating Schwann cells.

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Altered Connexin Expression after Peripheral Nerve Injury

Cited by 96 publications

References 0 publications

Transgenic Expression of HumanConnexin32in Myelinating Schwann Cells Prevents Demyelination inConnexin32-Null Mice

Transgenic Expression of HumanConnexin32in Myelinating Schwann Cells Prevents Demyelination inConnexin32-Null Mice

Connexin 48.5 Is Required for Normal Cardiovascular Function and Lens Development in Zebrafish Embryos

Prenylation-Defective Human Connexin32 Mutants Are Normally Localized and Function Equivalently to Wild-Type Connexin32 in Myelinating Schwann Cells

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