Background information. The BOR (branchio-oto-renal) syndrome is a dominant disorder most commonly caused by mutations in the EYA1 (Eyes Absent 1) gene. Symptoms commonly include deafness and renal anomalies.Results. We have used the embryos of the frog Xenopus laevis as an animal model for early ear development to examine the effects of different EYA1 mutations. Four eya1 mRNAs encoding proteins correlated with congenital anomalies in human were injected into early stage embryos. We show that the expression of mutations associated with BOR, even in the presence of normal levels of endogenous eya1 mRNA, leads to morphologically abnormal ear development as measured by overall otic vesicle size, establishment of sensory tissue and otic innervation. The molecular consequences of mutant eya1 expression were assessed by QPCR (quantitative PCR) analysis and in situ hybridization. Embryos expressing mutant eya1 showed altered levels of multiple genes (six1, dach, neuroD, ngnr-1 and nt3) important for normal ear development.Conclusions. These studies lend support to the hypothesis that dominant-negative effects of EYA1 mutations may have a role in the pathogenesis of BOR.
The large-conductance Ca(2+)-activated K(+) (BK) channel plays an essential role in maintaining uterine quiescence during pregnancy. Growing evidence has shown a link between the BK channel and bacterial lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) activation in macrophages. In the uterus, NF-κB activation plays an important role in inflammatory processes that lead to parturition. Our objective was to determine whether the BK channel regulates uterine contraction, in part, by modulating NF-κB translocation into the nucleus. We compared the effects of BK channel modulation to those of LPS on NF-κB nuclear translocation and contraction in an immortalized human myometrial cell line (human telomerase reverse transcriptase [hTERT]) and uterine myocytes. Our results showed that BK channel inhibitors paxilline and penitrem A induced translocation of NF-κB into the nucleus in both hTERT cells and uterine myocytes to a similar extent as LPS treatment, and LPS and paxilline similarly reduced BK channel currents. Conversely, neither BK channel openers nor blockade of the small conductance Ca(2+)-activated K(+) channel protein 3 had an effect on NF-κB translocation. Additionally, collagen-based assays showed that paxilline induced contraction of hTERT cells and uterine myocytes. This was dependent upon cyclooxygenase-2 activity. Moreover, paxilline-induced contractility and increased cyclooxygenase-2 expression both depended on availability of free NF-κB. This study suggests that BK channels regulate myometrial contraction, in part, by modulating nuclear translocation of NF-κB.
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