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30. Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics

Author

Dafinger, C, Liebau, M C, Elsayed, S M, Hellenbroich, Y, Boltshauser, E, Korenke, G C, Fabretti, F, Janecke, A R, Ebermann, I, Nürnberg, G, Nürnberg, P, Zentgraf, H, Koerber, F, Addicks, K, Elsobky, E, Benzing, T, Schermer, B, Bolz, H J, Dafinger, C, Liebau, M C, Elsayed, S M, Hellenbroich, Y, Boltshauser, E, Korenke, G C, Fabretti, F, Janecke, A R, Ebermann, I, Nürnberg, G, Nürnberg, P, Zentgraf, H, Koerber, F, Addicks, K, Elsobky, E, Benzing, T, Schermer, B, and Bolz, H J

Abstract

Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.

Published
2011

31. Irreversible inflammation is associated with decreased levels of the alpha1-, beta1-, and alpha2-subunits of sGC in human odontoblasts.

Author

Korkmaz Y, Lang H, Beikler T, Cho B, Behrends S, Bloch W, Addicks K, Raab WH, Korkmaz, Y, Lang, H, Beikler, T, Cho, B, Behrends, S, Bloch, W, Addicks, K, and Raab, W H-M

Abstract

The nitric oxide (NO) receptor enzyme soluble guanylate cyclase (sGC) contains one prosthetic heme group as an αβ heterodimer, and two heterodimer isoforms (α(1)β(1), α(2)β(1)) were characterized to have enzyme activity. To test the irreversible inflammation-dependent regulation of sGC in odontoblasts, we incubated decalcified frozen sections of healthy and inflamed human third molars with antibodies against β-actin, nitrotyrosine, inducible nitric oxide synthase (iNOS), α(1)-, β(1)-, and α(2)-subunits of sGC and analyzed them at protein levels by quantitative immunohistochemistry. The irreversible inflammation induced an increase in the signal intensities for nitrotyrosine and iNOS and a decrease for the α(1)-, β(1)-, and α(2)-subunits of sGC in odontoblasts. Inflammatory mediators, reactive oxygen, and nitrogen species may impair the expression of the α(1)-, β(1)-, and α(2)-subunits in odontoblasts. The decrease of sGC at the protein level in inflamed odontoblasts is compatible with a critical role for sGC to mediate biological effects of NO in health. [ABSTRACT FROM AUTHOR]

Published
2011
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33. Time-dependent activation of ERK1/2 in nerve terminals of the dentin-pulp complex following bradykinin treatment.

Author

Korkmaz Y, Bloch W, Schneider K, Zimmer S, Addicks K, Raab WH, Korkmaz, Y, Bloch, W, Schneider, K, Zimmer, S, Addicks, K, and Raab, W H-M

Abstract

The extracellular signal-regulated kinases 1 and 2 (ERK1/2) have been implicated in the inflammation-dependent sensitization of nociceptors, and the inflammatory mediator bradykinin (BK) led to a reduced threshold in the nociceptor terminals, activating intracellular signaling by phosphorylating receptors and ion channels. The effects of BK on the non-transcriptional modulation of the ERK1/2 in the peripheral nociceptor terminals, including in nerve endings of the dentin-pulp complex, are unknown. The time-dependent effects of BK (10(-7) M) on the ERK1/2 phosphorylation in nerve terminals of the dentin-pulp complex were investigated by quantitative and double immunolabeling with organ bath experiments. In nerve terminals, total and p-ERK1/2 were detected. In comparison with the controls, the numbers of p-ERK1/2-positive nerve endings increased after 1 and 3 min and decreased after 10 min of BK treatment. Analysis of the data indicates that BK induces phosphorylation-mediated local activation of ERK1/2 in nerve terminals modulating nociception in the dentin-pulp complex. [ABSTRACT FROM AUTHOR]

Published
2008
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