Connexins in the Nervous System

Abrams, Charles K.; Rash, John E.

doi:10.1007/978-1-59745-489-6_15

Cited by 7 publications

(8 citation statements)

References 225 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Connexins are a large family of homologous integral membrane proteins that form cell-cell channels or gap junctions as well as single-cell membrane hemichannels (Abrams and Rash, 2009; Kar et al, 2012) and provide a low resistance pathway for the diffusion of small molecules and ions between coupled cells (Kumar and Gilula, 1996). Recent data also suggests that connexins help regulate cell growth and apoptotic or necrotic cell death, independent of the formation of functional gap junction channels (Lin et al, 2003; Omori et al, 2007; Vinken et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves

Freidin

Asche-Godin

Abrams

2015

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

X-linked Charcot–Marie–Tooth disease (CMT1X) is an inherited peripheral neuropathy caused by mutations in GJB1, the human gene for Connexin32 (Cx32). This present study uses Ilumina Ref8-v2 BeadArray to examine the expression profiles of injured and uninjured sciatic nerves at 5, 7, and 14 days post-crush injury (dpi) from Wild Type (WT) and Cx32-knockout (Cx32KO) mice to identify the genes and signaling pathways that are dysregulated in the absence of Schwann cell Cx32. Given the assumption that loss of Schwann cell Cx32 disrupts the regeneration and maintenance of myelinated nerve leading to a demyelinating neuropathy in CMT1X, we initially hypothesized that nerve crush injury would result in significant increases in differential gene expression in Cx32KO mice relative to WT nerves. However, microarray analysis revealed a striking collapse in the number of differentially expressed genes at 5 and 7 dpi in Cx32KO nerves relative to WT, while uninjured and 14dpi time points showed large numbers of differentially regulated genes. Further comparisons within each genotype showed limited changes in Cx32KO gene expression following crush injury when compared to uninjured Cx32KO nerves. By contrast, WT nerves exhibited robust changes in gene expression at 5 and 7dpi with no significant differences in gene expression by 14dpi relative to uninjured WT nerve samples. Taken together, these data suggest the gene expression profile in uninjured Cx32KO sciatic nerve strongly resembles that of a WT nerve following injury and that loss of Schwann cell Cx32 leads to a basal state of gene expression similar to that of an injured WT nerve. These findings support a role for Cx32 in non-myelinating and regenerating populations of Schwann cells in normal axonal maintenance in re-myelination, and regeneration of peripheral nerve following injury. Disruption of Schwann cell-axonal communication in CMT1X may cause dysregulation of signaling pathways that are essential for the maintenance of intact myelinated peripheral nerves and to establish the necessary conditions for successful regeneration and remyelination following nerve injury.

show abstract

Section: Introductionmentioning

confidence: 99%

Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves

Freidin

Asche-Godin

Abrams

2015

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Here we emphasize the clinical phenotypes and current understanding of the pathogenesis of these genetic diseases, which will require a brief overview of connexin expression within CNS glial cells, reviewed in more detail elsewhere. [3, 4]…”

Section: Introductionmentioning

confidence: 99%

Gap junctions in inherited human disorders of the central nervous system

Abrams

Scherer

2012

Biochimica et Biophysica Acta (BBA) - Biomembranes

Self Cite

105

View full text Add to dashboard Cite

CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot-Marie-Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients with CMT1X. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6 months of life, cerebellar ataxia by 4 years, and spasticity by 6 years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann-Streiff syndrome, a disorder showing substantial overlap with ODDD.

show abstract

“…Experimental data indicate a surprisingly high degree of impact of deletion of Cx43 on other astrocyte genes, implying that gap junction gene expression alters numerous processes in addition to intercellular communication. Generally, mutations in connexin genes or altered expression of wild-type gap junction proteins may play important roles in the pathogenesis of various diseases not only of the central nervous system, but also of other organs, such as the heart (for review see [46]).…”

Section: Experimental Evidence For Downregulation Of Connexins and Upmentioning

confidence: 99%

Downregulation and Upregulation of Glial Connexins May Cause Synaptic Imbalances Responsible for the Pathophysiology of Bipolar Disorder

Mitterauer

2011

CNS Neuroscience & Therapeutics

View full text Add to dashboard Cite

The model of the pathophysiology of bipolar disorder proposed is based on imbalances in tripartite synapses caused by dysregulations of connexin expression in the astrocytic syncytium. If the expression of connexins is downregulated, a compensatory upregulation of astrocytic receptors may occur and be responsible for the pathophysiology of depression. Conversely, if the expression of connexins is upregulated, the expression of the astrocytic receptors may be downregulated and be responsible for the pathophysiology of mania. In depression, a relative lack of neurotransmitters exerts a protracted synaptic information processing, whereas in mania a relative increase of neurotransmitters may accelerate synaptic information processing. In addition, the modulatory role of gliotransmitters may be affected in bipolar disorder. Since the dysregulations of connexins impair the astrocytic syncytium, these disorders could be explanatory for cognitive impairment both in depression and in mania. Finally, the testability of this model is discussed.

show abstract

Connexins in the Nervous System

Cited by 7 publications

References 225 publications

Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves

Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves

Gap junctions in inherited human disorders of the central nervous system

Downregulation and Upregulation of Glial Connexins May Cause Synaptic Imbalances Responsible for the Pathophysiology of Bipolar Disorder

Contact Info

Product

Resources

About