title: Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis.
abstract: Notch signaling regulates tissue morphogenesis through cell-cell interactions. The Notch effectors Hes1 and Hes7 are expressed in an oscillatory manner and regulate developmental processes such as neurogenesis and somitogenesis, respectively. Expression of the mRNA for the mouse Notch ligand Delta-like1 (Dll1) is also oscillatory. However, the dynamics of Dll1 protein expression are controversial, and their functional significance is unknown. Here, we developed a live-imaging system and found that Dll1 protein expression oscillated in neural progenitors and presomitic mesoderm cells. Notably, when Dll1 expression was accelerated or delayed by shortening or elongating the Dll1 gene, Dll1 oscillations became severely dampened or quenched at intermediate levels, as modeled mathematically. Under this condition, Hes1 and Hes7 oscillations were also dampened. In the presomitic mesoderm, steady Dll1 expression led to severe fusion of somites and their derivatives, such as vertebrae and ribs. In the developing brain, steady Dll1 expression inhibited proliferation of neural progenitors and accelerated neurogenesis, whereas optogenetic induction of Dll1 oscillation efficiently maintained neural progenitors. These results indicate that the appropriate timing of Dll1 expression is critical for the oscillatory networks and suggest the functional significance of oscillatory cell-cell interactions in tissue morphogenesis.
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan; World Premier International Research Initiative-Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan;
authors.forename: Hiromi
authors.initials: H
authors.lastname: Shimojo
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Saitama 332-0012, Japan;
authors.forename: Akihiro
authors.initials: A
authors.lastname: Isomura
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan; Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan;
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ohtsuka
authors.affiliation: Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Saitama 332-0012, Japan; Department of Information Sciences, Ochanomizu University, Tokyo 112-8610, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kori
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyachi
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan; World Premier International Research Initiative-Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Saitama 332-0012, Japan; Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan;
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis / Q000502:physiology*; D009154:Mutation; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D019170:Somites / Q000196:embryology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D059008:Time-Lapse Imaging
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch
keywords: Dll1; neural development; oscillation; somite segmentation; time-lapse imaging