Oscillatory Expression of the bHLH Factor Hes1 Regulated by a Negative Feedback Loop

Hirata, Hiromi; Yoshiura, Shigeki; Ohtsuka, Toshiyuki; Bessho, Yasumasa; Harada, Takahiro; Yoshikawa, Kenichi; Kageyama, Ryoichiro

doi:10.1126/science.1074560

Cited by 685 publications

(802 citation statements)

References 26 publications

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“…Hes1 expression oscillates in many types of cultured cells, including fibroblasts, myoblasts, and neuroblasts, and the oscillatory expression can be induced following serum stimulation or Notch activation (Hirata et al, 2002;Masamizu et al, 2006). The period of Hes1 oscillation is about 2 h in many mouse cell lines.…”

Section: Hes1 Oscillation and Cell Proliferation In Cultured Cellsmentioning

confidence: 99%

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Kobayashi

Kageyama

2014

Current Topics in Developmental Biology

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Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1 to Hes7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences while the HLH region forms homo-and hetero-dimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits co-repressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate determination steps of embryonic stem cells and neural progenitor cells. Here we discuss some key features of Hes factors in development and diseases.

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Section: Hes1 Oscillation and Cell Proliferation In Cultured Cellsmentioning

confidence: 99%

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Kobayashi

Kageyama

2014

Current Topics in Developmental Biology

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“…Somitogenesis depends on a segmentation clock. The existence of a direct feedback inhibition loop, coupled with available experimental data (Hirata et al 2002), suggests that the oscillatory expression of Hes factors play a central role in maintaining the segmentation clock. Hes1 represses the transcription of its own gene through direct binding to regulatory sequences in the hes1 promoter.…”

Section: The Hes1 Systemmentioning

confidence: 99%

“…Examples include inflammation, meiosis, apoptosis and the heat shock response (Alberts et al 2008;Lahav et al 2004;Fall et al 2002). Experimental data reveal that pathways containing negative feedback loops exhibit sustained oscillations (Hirata et al 2002;Geva-Zatorsky et al 2006;Nelson et al 2004;Shankaran et al 2009). This is not unexpected given the interactions involved in a negative feedback loop.…”

Section: Introductionmentioning

confidence: 99%

Spatio-temporal modelling of the Hes1 and p53-Mdm2 intracellular signalling pathways

Sturrock

Terry

Xirodimas

et al. 2011

Journal of Theoretical Biology

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The correct localisation of transcription factors is vitally important for the proper functioning of many intracellular signalling pathways. Experimental data has shown that many pathways exhibit oscillations in concentrations of the substances involved, both temporally and spatially. Negative feedback loops are important components of these oscillations, providing fine regulation for the factors involved. In this paper we consider mathematical models of two such pathways -Hes1 and p53-Mdm2.Building on previous mathematical modelling approaches, we derive systems of partial differential equations to capture the evolution in space and time of the variables in the Hes1 and p53-Mdm2 systems. Through computational simulations we show that our reaction-diffusion models are able to produce sustained oscillations both spatially and temporally, accurately reflecting experimental evidence and advancing previous models. The simulations of our models also allow us to calculate a diffusion coefficient range for the variables in each mRNA and protein system, as well as ranges for other key parameters of the models, where sustained oscillations are observed. Finally, by exploiting the explicitly spatial nature of the partial differential equations, we are also able to manipulate mathematically the spatial location of the ribosomes, thus controlling where the proteins are synthesized within the cytoplasm. The results of these simulations predict an optimal distance outside the nucleus where protein synthesis should take place in order to generate sustained oscillations. Preprint submitted to Journal of Theoretical BiologyDecember 8, 2010 Using partial differential equation models, new information can be gained about the precise spatio-temporal dynamics of mRNA and proteins. The ability to determine spatial localisation of proteins within the cell is likely to yield fresh insight into a range of cellular diseases such as diabetes and cancer.

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“…The three proteins Hes1, p53, and NF-κB are transcriptionally regulated by short negative feedback loops and actual experiments have revealed that their genes show an oscillatory expression [1,2,3,4,5]. In the vertebrate segmentation clock several cycling genes are involved in an oscillatory mechanism driving somite segmentation [6].…”

Section: Introductionmentioning

confidence: 99%

“…In the vertebrate segmentation clock several cycling genes are involved in an oscillatory mechanism driving somite segmentation [6]. Mathematical models have been established for the regulation of these proteins [1,2,3,5,7,8,9,10,11,12] where the authors of [7,8,9,10] have introduced a discrete time delay to describe the time lag between transcription factor binding and gene transcription. Analytical and numerical results have shown that these models, which display damped oscillations for small positive delay times, can pass a Hopf bifurcation at a critical delay time where the stable steady state becomes unstable and a stable limit cycle oscillator emerges [7,8,9,10].…”

Section: Introductionmentioning

confidence: 99%

Intracellular delay limits cyclic changes in gene expression

Rateitschak

Wolkenhauer

2007

Mathematical Biosciences

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Based on previously published experimental observations and mathematical models for Hes1, p53 and NF-κB gene expression, we improve these models through a distributed delay formulation of the time lag between transcription factor binding and mRNA production. This description of natural variability for delays introduces a transition from a stable steady state to limit cycle oscillations and then a second transition back to a stable steady state which has not been observed in previously published models. On the basis of our results and following recent discussions about the role of delay-induced oscillations in gene transcription we establish the hypothesis that the period of the delay-induced cyclic changes should be characterized by an upper bound so that it cannot be greater then the period of fundamental biological cycles. We demonstrate our approach for two models. The first model describes Hes1 autorepression with equations for Hes1 mRNA production and Hes1 protein translation. The second model describes Hes1 repression by the protein complex Gro/TLE1/Hes1, where Gro/TLE1 is activated by Hes1 phosphorylation.

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Oscillatory Expression of the bHLH Factor Hes1 Regulated by a Negative Feedback Loop

Cited by 685 publications

References 26 publications

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Spatio-temporal modelling of the Hes1 and p53-Mdm2 intracellular signalling pathways

Intracellular delay limits cyclic changes in gene expression

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