title: Kcnh1 voltage-gated potassium channels are essential for early zebrafish development.
abstract: The Kcnh1 gene encodes a voltage-gated potassium channel highly expressed in neurons and involved in tumor cell proliferation, yet its physiological roles remain unclear. We have used the zebrafish as a model to analyze Kcnh1 function in vitro and in vivo. We found that the kcnh1 gene is duplicated in teleost fish (i.e. kcnh1a and kcnh1b) and that both genes are maternally expressed during early development. In adult zebrafish, kcnh1a and kcnh1b have distinct expression patterns but share expression in brain and testis. Heterologous expression of both genes in Xenopus oocytes revealed a strong conservation of characteristic functional properties between human and fish channels, including a unique sensitivity to intracellular Ca(2+)/calmodulin and modulation of voltage-dependent gating by extracellular Mg(2+). Using a morpholino antisense approach, we demonstrate a strong kcnh1 loss-of-function phenotype in developing zebrafish, characterized by growth retardation, delayed hindbrain formation, and embryonic lethality. This late phenotype was preceded by transcriptional up-regulation of known cell-cycle inhibitors (p21, p27, cdh2) and down-regulation of pro-proliferative factors, including cyclin D1, at 70% epiboly. These results reveal an unanticipated basic activity of kcnh1 that is crucial for early embryonic development and patterning.
authors.affiliation: Friedrich Schiller University of Jena and Jena University Hospital, Center for Molecular Biomedicine, Department of Biophysics.
authors.forename: Rayk
authors.initials: R
authors.lastname: Stengel
authors.affiliation: Leibniz Institute for Age Research-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Rivera-Milla
authors.affiliation: Friedrich Schiller University of Jena and Jena University Hospital, Center for Molecular Biomedicine, Department of Biophysics.
authors.forename: Nirakar
authors.initials: N
authors.lastname: Sahoo
authors.affiliation: Leibniz Institute for Age Research-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ebert
authors.affiliation: Leibniz Institute for Age Research-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bollig
authors.affiliation: Friedrich Schiller University of Jena and Jena University Hospital, Center for Molecular Biomedicine, Department of Biophysics.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Heinemann
authors.affiliation: Friedrich Schiller University of Jena and Jena University Hospital, Center for Molecular Biomedicine, Department of Biophysics. Electronic address: Roland.Schoenherr@uni-jena.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Schönherr
authors.affiliation: Leibniz Institute for Age Research-Fritz Lipmann Institute, D-07745 Jena, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Englert
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D008297:Male; D009928:Organ Specificity / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis* / Q000235:genetics; D012249:Rhombencephalon / Q000196:embryology; D014158:Transcription, Genetic / Q000502:physiology*; D014982:Xenopus laevis; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D024642:Potassium Channels, Voltage-Gated; D029961:Zebrafish Proteins; D019938:Cyclin D1