title: Transcript processing and export kinetics are rate-limiting steps in expressing vertebrate segmentation clock genes.
abstract: Sequential production of body segments in vertebrate embryos is regulated by a molecular oscillator (the segmentation clock) that drives cyclic transcription of genes involved in positioning intersegmental boundaries. Mathematical modeling indicates that the period of the clock depends on the total delay kinetics of a negative feedback circuit, including those associated with the synthesis of transcripts encoding clock components [Lewis J (2003) Curr Biol 13(16):1398-1408]. Here, we measure expression delays for three transcripts [Lunatic fringe, Hes7/her1, and Notch-regulated-ankyrin-repeat-protein (Nrarp)], that cycle during segmentation in the zebrafish, chick, and mouse, and provide in vivo measurements of endogenous splicing and export kinetics. We show that mRNA splicing and export are much slower than transcript elongation, with the longest delay (about 16 min in the mouse) being due to mRNA export. We conclude that the kinetics of mRNA and protein production and destruction can account for much of the clock period, and provide strong support for delayed autorepression as the underlying mechanism of the segmentation clock.
authors.affiliation: Cancer Research UK Developmental Genetics Laboratory, London Research Institute, London WC2A 3LY, United Kingdom.
authors.forename: Nathaniel P
authors.initials: NP
authors.lastname: Hoyle
authors.forename: David
authors.initials: D
authors.lastname: Ish-Horowicz
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001683:Biological Clocks / Q000502:physiology*; D019521:Body Patterning / Q000502:physiology*; D002460:Cell Line; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D016695:Glycosyltransferases / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D011506:Proteins / Q000378:metabolism; D012326:RNA Splicing / Q000502:physiology; D013045:Species Specificity; D013997:Time Factors; D015027:Zebrafish
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016695:Glycosyltransferases; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C430525:Hes7 protein, mouse; C499040:Nrarp protein, mouse; C498392:Lfng protein, mouse
keywords: RNA export; RNA splicing; mRNA processing; somites; transcriptional delays