{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:10:54Z","timestamp":1790097054341,"version":"4.0.1"},"reference-count":47,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/501100003382","name":"Core Research for Evolutional Science and Technology","doi-asserted-by":"publisher","award":["JPMJCR12W2"],"award-info":[{"award-number":["JPMJCR12W2"]}],"id":[{"id":"10.13039\/501100003382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["16H06480"],"award-info":[{"award-number":["16H06480"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K06254"],"award-info":[{"award-number":["18K06254"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The expression of the transcriptional repressor Hes1 oscillates in many cell types, including neural progenitor cells (NPCs), but the significance of Hes1 oscillations in development is not fully understood. To examine the effect of altered oscillatory dynamics of Hes1, we generated two types of Hes1 knock-in mice, a shortened (type-1) and an elongated (type-2) Hes1 gene, and examined their phenotypes focusing on neural development. While both mutations affected Hes1 oscillations, the type-1 mutation dampened Hes1 oscillations more severely, resulting in much lower amplitudes. The average levels of Hes1 expression in type-1-mutant NPCs were also lower than in wild-type NPCs but similar to or slightly higher than those in Hes1 heterozygous mutant mice, which exhibit no apparent defects. While type-2-mutant mice were apparently normal, type-1-mutant mice displayed smaller brains than wild-type mice and up-regulated proneural gene expression. Furthermore, proliferation of NPCs decreased and cell death increased in type-1-mutant embryos. When Hes3 and Hes5 were additionally deleted, neuronal differentiation was also accelerated, leading to microcephaly. Thus, robust Hes1 oscillations are required for maintenance and proliferation of NPCs and the normal timing of neurogenesis, thereby regulating brain morphogenesis.<\/jats:p>","DOI":"10.1242\/dev.182204","type":"journal-article","created":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T18:35:17Z","timestamp":1582569317000},"source":"Crossref","is-referenced-by-count":63,"title":["Oscillatory expression of Hes1 regulates cell proliferation and neuronal differentiation in the embryonic brain"],"prefix":"10.1242","author":[{"given":"Shohei","family":"Ochi","sequence":"first","affiliation":[{"name":"Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan"},{"name":"Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Imaizumi","sequence":"additional","affiliation":[{"name":"Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan"},{"name":"Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Shimojo","sequence":"additional","affiliation":[{"name":"Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Miyachi","sequence":"additional","affiliation":[{"name":"Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-1120","authenticated-orcid":false,"given":"Ryoichiro","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Institute for Frontier Life and Medical Sciences, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan"},{"name":"Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan"},{"name":"Kyoto University Graduate School of Biostudies, Kyoto 606-8501, Japan"},{"name":"Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042623010502800_DEV182204C1","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.molcel.2012.11.002","article-title":"Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals","volume":"49","author":"Albeck","year":"2013","journal-title":"Mol. Cell"},{"key":"2021042623010502800_DEV182204C2","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.molcel.2013.09.015","article-title":"Stochastic ERK activation induced by noise and cell-to-cell propagation regulates cell density-dependent proliferation","volume":"52","author":"Aoki","year":"2013","journal-title":"Mol. Cell"},{"key":"2021042623010502800_DEV182204C3","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1126\/science.1164860","article-title":"Pulsatile stimulation determines timing and specificity of NF-\u03baB-dependent transcription","volume":"324","author":"Ashall","year":"2009","journal-title":"Science"},{"key":"2021042623010502800_DEV182204C4","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1242\/dev.02403","article-title":"Persistent and high levels of Hes1 expression regulate boundary formation in the developing central nervous system","volume":"133","author":"Baek","year":"2006","journal-title":"Development"},{"key":"2021042623010502800_DEV182204C5","doi-asserted-by":"publisher","first-page":"3156","DOI":"10.1242\/dev.147256","article-title":"Hes5 regulates the transition timing of neurogenesis and gliogenesis in mammalian neocortical development","volume":"144","author":"Bansod","year":"2017","journal-title":"Development"},{"key":"2021042623010502800_DEV182204C6","doi-asserted-by":"publisher","first-page":"2642","DOI":"10.1101\/gad.930601","article-title":"Dynamic expression and essential functions of Hes7 in somite segmentation","volume":"15","author":"Bessho","year":"2001","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C7","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1101\/gad.1092303","article-title":"Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock","volume":"17","author":"Bessho","year":"2003","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C8","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.celrep.2012.05.017","article-title":"MicroRNA-9 modulates Hes1 ultradian oscillations by forming a double-negative feedback loop","volume":"2","author":"Bonev","year":"2012","journal-title":"Cell Rep."},{"key":"2021042623010502800_DEV182204C9","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1016\/j.cell.2018.06.007","article-title":"Evolution of cortical neurogenesis in amniotes controlled by Robo signaling levels","volume":"174","author":"C\u00e1rdenas","year":"2018","journal-title":"Cell"},{"key":"2021042623010502800_DEV182204C10","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1101\/gad.627811","article-title":"A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets","volume":"25","author":"Castro","year":"2011","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C11","doi-asserted-by":"publisher","first-page":"20100","DOI":"10.1074\/jbc.M117.815001","article-title":"The E3 ubiquitin ligase SCFFBXL14 complex stimulates neuronal differentiation by targeting the Notch signaling factor HES1 for proteolysis","volume":"292","author":"Chen","year":"2017","journal-title":"J. Biol. Chem."},{"key":"2021042623010502800_DEV182204C12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.celrep.2012.11.012","article-title":"Accelerating the tempo of the segmentation clock by reducing the number of introns in the Hes7 gene","volume":"3","author":"Harima","year":"2013","journal-title":"Cell Rep."},{"key":"2021042623010502800_DEV182204C13","doi-asserted-by":"publisher","first-page":"5539","DOI":"10.1242\/dev.01436","article-title":"Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation","volume":"131","author":"Hatakeyama","year":"2004","journal-title":"Development"},{"key":"2021042623010502800_DEV182204C14","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1146\/annurev-genet-112414-054639","article-title":"Nonsense-mediated mRNA decay: degradation of defective transcripts is only part of the story","volume":"49","author":"He","year":"2015","journal-title":"Annu. Rev. Genet."},{"key":"2021042623010502800_DEV182204C15","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1126\/science.1074560","article-title":"Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop","volume":"298","author":"Hirata","year":"2002","journal-title":"Science"},{"key":"2021042623010502800_DEV182204C16","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1038\/ng1372","article-title":"Instability of Hes7 protein is crucial for the somite segmentation clock","volume":"36","author":"Hirata","year":"2004","journal-title":"Nat. Genet."},{"key":"2021042623010502800_DEV182204C17","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1126\/science.1071914","article-title":"The I\u03baB\u2212NF-\u03baB signaling module: temporal control and selective gene activation","volume":"298","author":"Hoffmann","year":"2002","journal-title":"Science"},{"key":"2021042623010502800_DEV182204C18","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.neuron.2014.03.018","article-title":"bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells","volume":"82","author":"Imayoshi","year":"2014","journal-title":"Neuron"},{"key":"2021042623010502800_DEV182204C19","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1126\/science.1242366","article-title":"Oscillatory control of factors determining multipotency and fate in mouse neural progenitors","volume":"342","author":"Imayoshi","year":"2013","journal-title":"Science"},{"key":"2021042623010502800_DEV182204C20","doi-asserted-by":"publisher","first-page":"3136","DOI":"10.1101\/gad.9.24.3136","article-title":"Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects","volume":"9","author":"Ishibashi","year":"1995","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C21","doi-asserted-by":"publisher","first-page":"3627","DOI":"10.1242\/dev.104497","article-title":"Ultradian oscillations and pulses: coordinating cellular responses and cell fate decisions","volume":"141","author":"Isomura","year":"2014","journal-title":"Development"},{"key":"2021042623010502800_DEV182204C22","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.devcel.2019.01.009","article-title":"Signaling dynamics control cell fate in the early Drosophila embryo","volume":"48","author":"Johnson","year":"2019","journal-title":"Dev. Cell"},{"key":"2021042623010502800_DEV182204C23","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1242\/dev.127.7.1421","article-title":"Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm","volume":"127","author":"Jouve","year":"2000","journal-title":"Development"},{"key":"2021042623010502800_DEV182204C24","doi-asserted-by":"publisher","first-page":"3849","DOI":"10.1242\/dev.024570","article-title":"Selection of differentiating cells by different levels of delta-like 1 among neural precursor cells in the developing mouse telencephalon","volume":"135","author":"Kawaguchi","year":"2008","journal-title":"Development"},{"key":"2021042623010502800_DEV182204C25","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1101\/gad.1823109","article-title":"The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells","volume":"23","author":"Kobayashi","year":"2009","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C26","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1101\/gad.322818.118","article-title":"Oscillations of MyoD and Hes1 proteins regulate the maintenance of activated muscle stem cells","volume":"33","author":"Lahmann","year":"2019","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C27","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1126\/science.1239999","article-title":"Functional roles of pulsing in genetic circuits","volume":"342","author":"Levine","year":"2013","journal-title":"Science"},{"key":"2021042623010502800_DEV182204C28","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1016\/S0960-9822(03)00534-7","article-title":"Autoinhibition with transcriptional delay: a simple mechanism for the zebrafish somitogenesis oscillator","volume":"13","author":"Lewis","year":"2003","journal-title":"Curr. Biol."},{"key":"2021042623010502800_DEV182204C29","doi-asserted-by":"publisher","first-page":"2835","DOI":"10.1038\/s41467-019-10734-8","article-title":"Quantitative single-cell live imaging links HES5 dynamics with cell-state and fate in murine neurogenesis","volume":"10","author":"Manning","year":"2019","journal-title":"Nat. Commun."},{"key":"2021042623010502800_DEV182204C30","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1073\/pnas.0508658103","article-title":"Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells","volume":"103","author":"Masamizu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042623010502800_DEV182204C31","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1016\/S0960-9822(03)00494-9","article-title":"Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays","volume":"19","author":"Monk","year":"2003","journal-title":"Curr. Biol."},{"key":"2021042623010502800_DEV182204C32","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1126\/science.1099962","article-title":"Oscillations in NF-\u03baB signaling control the dynamics of gene expression","volume":"306","author":"Nelson","year":"2004","journal-title":"Science"},{"key":"2021042623010502800_DEV182204C33","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1242\/dev.063735","article-title":"Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock","volume":"139","author":"Oates","year":"2012","journal-title":"Development"},{"key":"2021042623010502800_DEV182204C34","doi-asserted-by":"publisher","first-page":"2196","DOI":"10.1093\/emboj\/18.8.2196","article-title":"Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation","volume":"18","author":"Ohtsuka","year":"1999","journal-title":"EMBO J."},{"key":"2021042623010502800_DEV182204C35","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.mcn.2005.09.006","article-title":"Visualization of embryonic neural stem cells using Hes promoters in transgenic mice","volume":"31","author":"Ohtsuka","year":"2006","journal-title":"Mol. Cell. Neurosci."},{"key":"2021042623010502800_DEV182204C36","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.cell.2011.05.011","article-title":"Vertebrate segmentation: from cyclic gene networks to scoliosis","volume":"145","author":"Pourqui\u00e9","year":"2011","journal-title":"Cell"},{"key":"2021042623010502800_DEV182204C37","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/j.cell.2013.02.005","article-title":"Encoding and decoding cellular information through signaling dynamics","volume":"152","author":"Purvis","year":"2013","journal-title":"Cell"},{"key":"2021042623010502800_DEV182204C38","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1126\/science.1155998","article-title":"Control of the reversibility of cellular quiescence by the transcriptional repressor HES1","volume":"321","author":"Sang","year":"2008","journal-title":"Science"},{"key":"2021042623010502800_DEV182204C39","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.neuron.2008.02.014","article-title":"Oscillations in Notch signaling regulate maintenance of neural progenitors","volume":"58","author":"Shimojo","year":"2008","journal-title":"Neuron"},{"key":"2021042623010502800_DEV182204C40","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1101\/gad.270785.115","article-title":"Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis","volume":"30","author":"Shimojo","year":"2016","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C41","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1101\/gad.323196.118","article-title":"High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain","volume":"33","author":"Sueda","year":"2019","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C42","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.devcel.2008.02.002","article-title":"Intron delays and transcriptional timing during development","volume":"14","author":"Swinburne","year":"2008","journal-title":"Dev. Cell"},{"key":"2021042623010502800_DEV182204C43","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1101\/gad.1696108","article-title":"Intron length increases oscillatory periods of gene expression in animal cells","volume":"22","author":"Swinburne","year":"2008","journal-title":"Genes Dev."},{"key":"2021042623010502800_DEV182204C44","doi-asserted-by":"publisher","first-page":"3300","DOI":"10.1073\/pnas.1014418108","article-title":"Intronic delay is essential for oscillatory expression in the segmentation clock","volume":"108","author":"Takashima","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042623010502800_DEV182204C45","doi-asserted-by":"publisher","first-page":"e08438","DOI":"10.7554\/eLife.08438","article-title":"Persistence, period and precision of autonomous cellular oscillators from the zebrafish segmentation clock","volume":"5","author":"Webb","year":"2016","journal-title":"eLife"},{"key":"2021042623010502800_DEV182204C46","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1882-z","article-title":"Control of coupling delay for synchronized oscillations in the segmentation clock","author":"Yoshioka-Kobayashi","year":"2020","journal-title":"Nature"},{"key":"2021042623010502800_DEV182204C47","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1634\/stemcells.2005-0598","article-title":"HES1 inhibits cycling of hematopoietic progenitor cells via DNA binding","volume":"24","author":"Yu","year":"2006","journal-title":"Stem Cells"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.182204","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.182204\/1971558\/dev182204.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.182204\/2064563\/dev_182204v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.182204\/2064563\/dev_182204v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T18:57:15Z","timestamp":1621364235000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.182204\/266856\/Oscillatory-expression-of-Hes1-regulates-cell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":47,"URL":"https:\/\/doi.org\/10.1242\/dev.182204","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2020,1,1]]},"article-number":"dev.182204"}}