• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Apr 15, 1999; 18(8): 2196–2207.
PMCID: PMC1171303

Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation.

Abstract

While the transmembrane protein Notch plays an important role in various aspects of development, and diseases including tumors and neurological disorders, the intracellular pathway of mammalian Notch remains very elusive. To understand the intracellular pathway of mammalian Notch, the role of the bHLH genes Hes1 and Hes5 (mammalian hairy and Enhancer-of-split homologues) was examined by retrovirally misexpressing the constitutively active form of Notch (caNotch) in neural precursor cells prepared from wild-type, Hes1-null, Hes5-null and Hes1-Hes5 double-null mouse embryos. We found that caNotch, which induced the endogenous Hes1 and Hes5 expression, inhibited neuronal differentiation in the wild-type, Hes1-null and Hes5-null background, but not in the Hes1-Hes5 double-null background. These results demonstrate that Hes1 and Hes5 are essential Notch effectors in regulation of mammalian neuronal differentiation.

Full Text

The Full Text of this article is available as a PDF (870K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Akazawa C, Sasai Y, Nakanishi S, Kageyama R. Molecular characterization of a rat negative regulator with a basic helix-loop-helix structure predominantly expressed in the developing nervous system. J Biol Chem. 1992 Oct 25;267(30):21879–21885. [PubMed]
  • Akazawa C, Ishibashi M, Shimizu C, Nakanishi S, Kageyama R. A mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system. J Biol Chem. 1995 Apr 14;270(15):8730–8738. [PubMed]
  • Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science. 1995 Apr 14;268(5208):225–232. [PubMed]
  • Bao ZZ, Cepko CL. The expression and function of Notch pathway genes in the developing rat eye. J Neurosci. 1997 Feb 15;17(4):1425–1434. [PubMed]
  • Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, Guo Q, Matzuk MM, Zoghbi HY. Math1 is essential for genesis of cerebellar granule neurons. Nature. 1997 Nov 13;390(6656):169–172. [PubMed]
  • Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S. Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell. 1997 Jul 25;90(2):281–291. [PubMed]
  • Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S, Bishop JM. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Mol Cell Biol. 1997 Nov;17(11):6265–6273. [PMC free article] [PubMed]
  • Casarosa S, Fode C, Guillemot F. Mash1 regulates neurogenesis in the ventral telencephalon. Development. 1999 Feb;126(3):525–534. [PubMed]
  • Cau E, Gradwohl G, Fode C, Guillemot F. Mash1 activates a cascade of bHLH regulators in olfactory neuron progenitors. Development. 1997 Apr;124(8):1611–1621. [PubMed]
  • Chen H, Thiagalingam A, Chopra H, Borges MW, Feder JN, Nelkin BD, Baylin SB, Ball DW. 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. 1997 May 13;94(10):5355–5360. [PMC free article] [PubMed]
  • Conlon RA, Reaume AG, Rossant J. Notch1 is required for the coordinate segmentation of somites. Development. 1995 May;121(5):1533–1545. [PubMed]
  • Hrabe de Angelis M, McIntyre J, 2nd, Gossler A. Maintenance of somite borders in mice requires the Delta homologue DII1. Nature. 1997 Apr 17;386(6626):717–721. [PubMed]
  • de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, et al. Conservation of the Notch signalling pathway in mammalian neurogenesis. Development. 1997 Mar;124(6):1139–1148. [PubMed]
  • Dorsky RI, Chang WS, Rapaport DH, Harris WA. Regulation of neuronal diversity in the Xenopus retina by Delta signalling. Nature. 1997 Jan 2;385(6611):67–70. [PubMed]
  • Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991 Aug 23;66(4):649–661. [PubMed]
  • Fode C, Gradwohl G, Morin X, Dierich A, LeMeur M, Goridis C, Guillemot F. The bHLH protein NEUROGENIN 2 is a determination factor for epibranchial placode-derived sensory neurons. Neuron. 1998 Mar;20(3):483–494. [PubMed]
  • Gridley T. Notch signaling in vertebrate development and disease. Mol Cell Neurosci. 1997;9(2):103–108. [PubMed]
  • Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ, Joyner AL. Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell. 1993 Nov 5;75(3):463–476. [PubMed]
  • Honjo T. The shortest path from the surface to the nucleus: RBP-J kappa/Su(H) transcription factor. Genes Cells. 1996 Jan;1(1):1–9. [PubMed]
  • Hsieh JJ, Nofziger DE, Weinmaster G, Hayward SD. Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation. J Virol. 1997 Mar;71(3):1938–1945. [PMC free article] [PubMed]
  • Ishibashi M, Moriyoshi K, Sasai Y, Shiota K, Nakanishi S, Kageyama R. Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J. 1994 Apr 15;13(8):1799–1805. [PMC free article] [PubMed]
  • Ishibashi M, Ang SL, Shiota K, Nakanishi S, Kageyama R, Guillemot F. 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. 1995 Dec 15;9(24):3136–3148. [PubMed]
  • Issack PS, Ziff EB. Genetic elements regulating HES-1 induction in Wnt-1-transformed PC12 cells. Cell Growth Differ. 1998 Oct;9(10):827–836. [PubMed]
  • Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995 Sep 28;377(6547):355–358. [PubMed]
  • Jarriault S, Le Bail O, Hirsinger E, Pourquié O, Logeat F, Strong CF, Brou C, Seidah NG, Isra l A. Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol Cell Biol. 1998 Dec;18(12):7423–7431. [PMC free article] [PubMed]
  • Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino G, Callahan R. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev. 1992 Mar;6(3):345–355. [PubMed]
  • Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996 Oct 24;383(6602):707–710. [PubMed]
  • Kageyama R, Nakanishi S. Helix-loop-helix factors in growth and differentiation of the vertebrate nervous system. Curr Opin Genet Dev. 1997 Oct;7(5):659–665. [PubMed]
  • Kopan R, Nye JS, Weintraub H. The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development. 1994 Sep;120(9):2385–2396. [PubMed]
  • Kopan R, Schroeter EH, Weintraub H, Nye JS. Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1683–1688. [PMC free article] [PubMed]
  • Lecourtois M, Schweisguth F. Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos. Curr Biol. 1998 Jun 18;8(13):771–774. [PubMed]
  • Lewis J. Neurogenic genes and vertebrate neurogenesis. Curr Opin Neurobiol. 1996 Feb;6(1):3–10. [PubMed]
  • Luo B, Aster JC, Hasserjian RP, Kuo F, Sklar J. Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol Cell Biol. 1997 Oct;17(10):6057–6067. [PMC free article] [PubMed]
  • Ma Q, Chen Z, del Barco Barrantes I, de la Pompa JL, Anderson DJ. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron. 1998 Mar;20(3):469–482. [PubMed]
  • Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P, Kadesch T, Artavanis-Tsakonas S. Human deltex is a conserved regulator of Notch signalling. Nat Genet. 1998 May;19(1):74–78. [PubMed]
  • Milner LA, Bigas A, Kopan R, Brashem-Stein C, Bernstein ID, Martin DI. Inhibition of granulocytic differentiation by mNotch1. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13014–13019. [PMC free article] [PubMed]
  • Nishimura M, Isaka F, Ishibashi M, Tomita K, Tsuda H, Nakanishi S, Kageyama R. Structure, chromosomal locus, and promoter of mouse Hes2 gene, a homologue of Drosophila hairy and Enhancer of split. Genomics. 1998 Apr 1;49(1):69–75. [PubMed]
  • Nye JS, Kopan R, Axel R. An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells. Development. 1994 Sep;120(9):2421–2430. [PubMed]
  • Ordentlich P, Lin A, Shen CP, Blaumueller C, Matsuno K, Artavanis-Tsakonas S, Kadesch T. Notch inhibition of E47 supports the existence of a novel signaling pathway. Mol Cell Biol. 1998 Apr;18(4):2230–2239. [PMC free article] [PubMed]
  • Pan D, Rubin GM. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell. 1997 Jul 25;90(2):271–280. [PubMed]
  • Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J, Baltimore D. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996 May 1;183(5):2283–2291. [PMC free article] [PubMed]
  • Robey E, Chang D, Itano A, Cado D, Alexander H, Lans D, Weinmaster G, Salmon P. An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell. 1996 Nov 1;87(3):483–492. [PubMed]
  • Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S. Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev. 1992 Dec;6(12B):2620–2634. [PubMed]
  • Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998 May 28;393(6683):382–386. [PubMed]
  • Shawber C, Nofziger D, Hsieh JJ, Lindsell C, Bögler O, Hayward D, Weinmaster G. Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway. Development. 1996 Dec;122(12):3765–3773. [PubMed]
  • Sommer L, Shah N, Rao M, Anderson DJ. The cellular function of MASH1 in autonomic neurogenesis. Neuron. 1995 Dec;15(6):1245–1258. [PubMed]
  • Sparrow JR, Hicks D, Barnstable CJ. Cell commitment and differentiation in explants of embryonic rat neural retina. Comparison with the developmental potential of dissociated retina. Brain Res Dev Brain Res. 1990 Jan 1;51(1):69–84. [PubMed]
  • Struhl G, Adachi A. Nuclear access and action of notch in vivo. Cell. 1998 May 15;93(4):649–660. [PubMed]
  • Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T. Notch1 is essential for postimplantation development in mice. Genes Dev. 1994 Mar 15;8(6):707–719. [PubMed]
  • Takebayashi K, Sasai Y, Sakai Y, Watanabe T, Nakanishi S, Kageyama R. Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-1. Negative autoregulation through the multiple N box elements. J Biol Chem. 1994 Feb 18;269(7):5150–5156. [PubMed]
  • Takebayashi K, Akazawa C, Nakanishi S, Kageyama R. Structure and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-5. Identification of the neural precursor cell-specific promoter element. J Biol Chem. 1995 Jan 20;270(3):1342–1349. [PubMed]
  • Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, Honjo T. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol. 1995 Dec 1;5(12):1416–1423. [PubMed]
  • Tomita K, Ishibashi M, Nakahara K, Ang SL, Nakanishi S, Guillemot F, Kageyama R. Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron. 1996 Apr;16(4):723–734. [PubMed]
  • Tomita K, Nakanishi S, Guillemot F, Kageyama R. Mash1 promotes neuronal differentiation in the retina. Genes Cells. 1996 Aug;1(8):765–774. [PubMed]
  • Tsuda H, Takebayashi K, Nakanishi S, Kageyama R. Structure and promoter analysis of Math3 gene, a mouse homolog of Drosophila proneural gene atonal. Neural-specific expression by dual promoter elements. J Biol Chem. 1998 Mar 13;273(11):6327–6333. [PubMed]
  • Turner DL, Cepko CL. A common progenitor for neurons and glia persists in rat retina late in development. Nature. 1987 Jul 9;328(6126):131–136. [PubMed]
  • Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, Weinmaster G, Barres BA. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron. 1998 Jul;21(1):63–75. [PubMed]
  • Weinmaster G. The ins and outs of notch signaling. Mol Cell Neurosci. 1997;9(2):91–102. [PubMed]
  • Yoshimatsu T, Tamura M, Kuriyama S, Ikenaka K. Improvement of retroviral packaging cell lines by introducing the polyomavirus early region. Hum Gene Ther. 1998 Jan 20;9(2):161–172. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Gene
    Gene
    Gene links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...