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Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear

Ortolano, Saida ; Di Pasquale, Giovanni ; Crispino, Giulia ; Anselmi, Fabio ; Mammano, Fabio ; Chiorini, John A

Proceedings of the National Academy of Sciences - PNAS, 2008-12, Vol.105 (48), p.18776-18781 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear
Autor: Ortolano, Saida ; Di Pasquale, Giovanni ; Crispino, Giulia ; Anselmi, Fabio ; Mammano, Fabio ; Chiorini, John A
Assuntos: Animals ; Biological Sciences ; Bovine adeno-associated virus ; Calcium ; Calcium - metabolism ; Calcium Signaling - physiology ; Cattle ; Cell culture ; Cells ; Cochlea ; Connexin 26 ; Connexin 30 ; Connexins ; Connexins - genetics ; Connexins - metabolism ; Cultured cells ; Deafness ; Deafness - genetics ; Ear, Inner - cytology ; Ear, Inner - metabolism ; Ears & hearing ; Epithelial cells ; Gap junctions ; Gene expression ; Hair cells ; Humans ; Inner ear ; Messenger RNA ; Mice ; Mice, Knockout ; NF-kappa B - metabolism ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - metabolism ; Rodents ; Tissue Culture Techniques
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2008-12, Vol.105 (48), p.18776-18781
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Author contributions: F.M. and J.A.C. designed research; S.O., G.D.P., G.C., and F.A. performed research; S.O., G.D.P., F.M., and J.A.C. contributed new reagents/analytic tools; S.O., F.A., and F.M. analyzed data; and F.M. and J.A.C. wrote the paper.
Edited by Michael V. L. Bennett, Albert Einstein College of Medicine, Bronx, NY, and approved September 26, 2008
1S.O. and G.D.P. contributed equally to this work.
Descrição: Connexin 26 (Cx26) and connexin 30 (Cx30) are encoded by two genes (GJB2 and GJB6, respectively) that are found within 50 kb in the same complex deafness locus, DFNB1. Immunocytochemistry and quantitative PCR analysis of Cx30 KO mouse cultures revealed that Cx26 is downregulated at the protein level and at the mRNA level in nonsensory cells located between outer hair cells and the stria vascularis. To explore connexin coregulation, we manipulated gene expression using the bovine adeno-associated virus. Overexpression of Cx30 in the Cx30 KO mouse by transduction with bovine adeno-associated virus restored Cx26 expression, permitted the formation of functional gap junction channels, and rescued propagating Ca²⁺ signals. Ablation of Cx26 by transduction of Cx26loxP/loxP cultures with a Cre recombinase vector caused concurrent downregulation of Cx30 and impaired intercellular communication. The coordinated regulation of Cx26 and Cx30 expression appears to occur as a result of signaling through PLC and the NF-κB pathway, because activation of IP₃-mediated Ca²⁺ responses by stimulation of P2Y receptors for 20 min with 20 nM ATP increased the levels of Cx26 transcripts in Cx30 KO cultures. This effect was inhibited by expressing a stable form of the IκB repressor protein that prevents activation/translocation of NF-κB. Thus, our data reveal a Ca²⁺-dependent control in the expression of inner ear connexins implicated in hereditary deafness as well as insight into the hitherto unexplained observation that some deafness-associated DFNB1 alleles are characterized by hereditable reduction of both GJB2 and GJB6 expression.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear

Ortolano, Saida ; Di Pasquale, Giovanni ; Crispino, Giulia ; Anselmi, Fabio ; Mammano, Fabio ; Chiorini, John A

United States: National Academy of Sciences

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