Abstract
The Notch effectors Hes1 and Hes7 and the Notch ligand Delta-like1 (Dll1) are expressed in an oscillatory manner during neurogenesis and somitogenesis. These two biological events exhibit different types of oscillations: anti-/out-of-phase oscillation in neural stem cells during neurogenesis and in-phase oscillation in presomitic mesoderm (PSM) cells during somitogenesis. Accelerated or delayed Dll1 expression by shortening or elongating the size of the Dll1 gene, respectively, dampens or quenches Dll1 oscillation at intermediate levels, a phenomenon known as “amplitude/oscillation death” of coupled oscillators. Under this condition, both Hes1 oscillation in neural stem cells and Hes7 oscillation in PSM cells are also dampened. As a result, maintenance of neural stem cells is impaired, leading to microcephaly, while somite segmentation is impaired, leading to severe fusion of somites and their derivatives, such as vertebrae and ribs. Thus, the appropriate timing of Dll1 expression is critical for the oscillatory expression in Notch signaling and normal processes of neurogenesis and somitogenesis. Optogenetic analysis indicated that Dll1 oscillations transfer the oscillatory information between neighboring cells, which may induce anti−/out-of-phase and in-phase oscillations depending on the delay in signaling transmission. These oscillatory dynamics can be described in a unified manner by mathematical modeling.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alvarez-Buylla A, Garcia-Verdugo JM, Tramontin AD (2001) A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2:287–293
Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776
Aster JC, Pear WS, Blacklow SC (2016) The varied roles of notch in cancer. Annu Rev Pathol 12:245–275
Bessho Y, Sakata R, Komatsu S, Shiota K, Yamada S, Kageyama R (2001) Dynamic expression and essential functions of Hes7 in somite segmentation. Genes Dev 15:2642–2647
Bessho Y, Hirata H, Masamizu Y, Kageyama R (2003) Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev 17:1451–1456
Bettenhausen B, Hrabe de Angelis M, Simon D, Guenet JL, Gossler A (1995) Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development 121:2407–2418
Bone RA, Bailey CSL, Wiedermann G, Ferjentsik Z, Appleton PL, Murray PJ, Maroto M, Dale JK (2014) Spatiotemporal oscillations of Notch1, Dll1 and NICD are coordinated across the mouse PSM. Development 141:4806–4816
Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol 17:722–735
Castro DS, Martynoga B, Parras C, Ramesh V, Pacary E, Johnston C, Drechsel D, Lebel-Potter M, Garcia LG, Hunt C et al (2011) A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets. Genes Dev 25:930–945
Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB, Ball DW (1997) Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proc Natl Acad Sci U S A 94:5355–5360
Delaune EA, François P, Shih NP, Amacher SL (2012) Single-cell-resolution imaging of the impact of notch signaing and mitosis on segmentation clock dynamics. Dev Cell 23:995–1005
Evrard YA, Lun Y, Aulehla A, Gan L, Johnson RL (1998) lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394:377–381
Fishell G, Kriegstein AR (2003) Neurons from radial glia: the consequences of asymmetric inheritance. Curr Opin Neurobiol 13:34–41
Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16:633–647
Fujita S (2003) The discovery of the matrix cell, the identification of the multipotent neural stem cell and the development of the central nervous system. Cell Struct Funct 28:205–228
Gaiano N, Fishell G (2002) The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 25:471–490
Giudicelli F, Ozbudak EM, Wright GJ, Lewis J (2007) Setting the tempo in development: an investigation of the zebrafish somite clock mechanism. PLoS Biol 5:e150
Götz M, Huttner WB (2005) The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6:777–788
Harima Y, Takashima Y, Ueda Y, Ohtsuka T, Kageyama R (2013) Accelerating the tempo of the segmentation clock by reducing the number of introns in the Hes7 gene. Cell Rep 3:1–7
Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R (2004) Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131:5539–5550
Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K, Kageyama R (2002) Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science 298:840–843
Horikawa K, Ishimatsu K, Yoshimoto E, Kondo S, Takeda H (2006) Noise-resistant and synchronized oscillation of the segmentation clock. Nature 441:719–723
Hrabe de Angelis M, McIntyre J II, Gossler A (1997) Maintenance of somite borders in mice requires the Delta homologue Dll1. Nature 386:717–721
Imayoshi I, Kageyama R (2014) bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells. Neuron 82:9–23
Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H, Fujiwara TK, Ishidate F, Kageyama R (2013) Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science 342:1203–1208
Ishibashi M, Moriyoshi K, Sasai Y, Shiota K, Nakanishi S, Kageyama R (1994) Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J 13:1799–1805
Ishibashi M, Ang SL, Shiota K, Nakanishi S, Kageyama R, Guillemot F (1995) 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. Genes Dev 9:3136–3148
Isomura A, Ogushi F, Kori H, Kageyama R (2017) Optogenetic perturbation and bioluminescence imaging to analyze cell-to-cell transfer of oscillatory information. Genes Dev 31:524–535
Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A (1995) Signalling downstream of activated mammalian notch. Nature 377:355–358
Jiang Y-J, Aerne BL, Smithers L, Haddon C, Ish-Horowicz D, Lewis J (2000) Notch signaling and the synchronization of the somite segmentation clock. Nature 408:475–479
Kageyama R, Ohtsuka T, Shimojo H, Imayoshi I (2008) Dynamic notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat Neurosci 11:1247–1251
Kopan R, Ilagan MXG (2009) The canonical notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233
Mara A, Schroeder J, Chalouni C, Holley SA (2007) Priming, initiation and synchronization of the segmentation clock by deltaD and deltaC. Nat Cell Biol 9:523–530
Maroto M, Dale JK, Dequéant M-L, Petit A-C, Pourquié O (2005) Synchronised cycling gene oscillations in presomitic mesoderm cells require cell-cell contact. Int J Dev Biol 49:309–315
Maruhashi M, Van de Putte T, Huylebroeck D, Kondoh H, Higashi Y (2005) Involvement of SIP1 in positioning of somite boundaries in the mouse embryo. Dev Dyn 234:332–338
Masamizu Y, Ohtsuka T, Takashima Y, Nagahara H, Takenaka Y, Yoshikawa K, Okamura H, Kageyama R (2006) Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells. Proc Natl Acad Sci U S A 103:1313–1318
Miller ED, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54:357–369
Niwa Y, Shimojo H, Isomura A, González A, Miyachi H, Kageyama R (2011) Different types of oscillations in notch and Fgf signaling regulate the spatiotemporal periodicity of somitogenesis. Genes Dev 25:1115–1120
Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot F, Kageyama R (1999) Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J 18:2196–2207
Ohtsuka T, Sakamoto M, Guillemot F, Kageyama R (2001) Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J Biol Chem 276:30467–30474
Okubo Y, Sugawara T, Abe-Koduka N, Kanno J, Kimura A, Saga Y (2012) Lfng regulates the synchronized oscillation of the mouse segmentation clock via trans-repression of notch signalling. Nat Commun 3:1141
Özbudak EM, Lewis J (2008) Notch signaling synchronizes the zebrafish segmentation clock but is not needed to create somite boundaries. PLoS Genet 4:e15
Panin VM, Shao L, Lei L, Moloney DJ, Irvine KD, Haltiwanger RS (2002) Notch ligands are substrates for protein O-fucosyltransferase-1 and fringe. J Biol Chem 277:29945–29952
Pierfelice T, Alberi L, Gaiano N (2011) Notch in the vertebrate nervous system: an old dog with new tricks. Neuron 69:840–855
Pourquié O (2011) Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell 145:650–663
Ramana Reddy DV, Sen A, Johnston GL (1998) Experimental evidence of time delay induced death in coupled limit cycle oscillators. Phys Rev Lett 80:5109–5112
Riedel-Kruse IH, Müller C, Oates AC (2007) Synchrony dynamics during initiation, failure, and rescue of the segmentation clock. Science 317:1911–1915
Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58:52–64
Shimojo H, Isomura A, Ohtsuka T, Kori H, Miyachi H, Kageyama R (2016) Oscillatory control of Delta-like1 in cell interactions regulate dynamic gene expression and tissue morphogenesis. Genes Dev 30:102–116
Sparrow DB, Chapman G, Smith AJ, Mattar MZ, Major JA, O’Reilly VC, Saga Y, Zackai EH, Dormans JP, Alman BA, McGregor L, Kageyama R, Kusumi K, Dunwoodie SL (2012) A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell 149:295–306
Takashima Y, Ohtsuka T, González A, Miyachi H, Kageyama R (2011) Intronic delay is essential for oscillatory expression in the segmentation clock. Proc Natl Acad Sci U S A 108:3300–3305
Tsiairis CD, Aulehla A (2016) Self-organization of embryonic genetic oscillators into spatiotemporal wave patterns. Cell 164:656–667
Wang X, Chen X, Yang Y (2012) Spatiotemporal control of gene expression by a light-switchable transgene system. Nat Methods 9:266–269
Zhang N, Gridley T (1998) Defects in somite formation in lunatic fringe-deficient mice. Nature 394:374–377
Acknowledgements
This work was supported by Core Research for Evolutional Science and Technology (R.K.), Grant-in-Aid for Scientific Research on Innovative Areas (MEXT 16H06480 to R.K., MEXT 24116705 to H.S., and MEXT 26119708 to A.I.), Scientific Research (A) (JSPS 24240049) (R.K.), Young Scientists (A) (JSPS 15H05326) (A.I.) and Young Scientists (B) (JSPS 24700354) (H.S.) and Platform for Dynamic Approaches to Living System from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Kageyama, R., Shimojo, H., Isomura, A. (2018). Oscillatory Control of Notch Signaling in Development. In: Borggrefe, T., Giaimo, B. (eds) Molecular Mechanisms of Notch Signaling. Advances in Experimental Medicine and Biology, vol 1066. Springer, Cham. https://doi.org/10.1007/978-3-319-89512-3_13
Download citation
DOI: https://doi.org/10.1007/978-3-319-89512-3_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-89511-6
Online ISBN: 978-3-319-89512-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)