CoChat
Sign Up
Cited by 579Gene Regulatory Network AnalysisDevelopmental Biology and Gene RegulationGenomics and Chromatin Dynamics

Emerging properties of animal gene regulatory networks

Open access
Davidson, Eric H.·2010·Nature
DOI 10.1038/nature09645PMC PMC3967874
Open this paper in CoChat — free accountOpen PDF

Abstract

Gene regulatory networks (GRNs) provide system level explanations of developmental and physiological functions in the terms of the genomic regulatory code. Depending on their developmental functions, GRNs differ in their degree of hierarchy, and also in the types of modular sub-circuit of which they are composed, although there is a commonly employed sub-circuit repertoire. Mathematical modelling of some types of GRN sub-circuit has deepened biological understanding of the functions they mediate. The structural organization of various kinds of GRN reflects their roles in the life process, and causally illuminates both developmental and evolutionary process.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that animal gene regulatory networks (GRNs) are assembled from a limited repertoire of modular sub-circuit topologies, while their global depth and hierarchy vary with biological function. It synthesizes developmental, physiological, evolutionary, and modeling evidence to propose that GRN structure causally explains both ontogeny and body-plan evolution.

Key findings

  • GRNs are modular: a small, finite set of sub-circuit topologies likely underlies developmental programs, and structurally similar circuits built from different regulatory genes perform similar jobs. Table 1 compiles examples, including a double-negative gate that acts as an X,1−X spatial processor.
  • Embryonic specification GRNs are deep and hierarchical. The sea urchin endomesoderm GRN is the reference; its skeletogenic lineage portion contains 24 regulatory genes plus signalling and differentiation genes, with layered sub-circuits for spatial input, state lockdown, signalling, exclusion, and differentiation activation. Body-part and organ GRNs are similarly deep, often using positive feedback to lock regulatory states and signal-mediated mutual repression across cellular boundaries.
  • Postembryonic haematopoietic binary fate choices use relatively shallow cross-antagonistic repressor pairs near terminal differentiation; lineage priming occurs in stem cells but not in embryonic fate choices. Differentiation gene batteries are shallow and often coherent feedforward, whereas morphogenetic cassettes may control only a few key genes that nucleate a process.
  • Mathematical models of sub-circuits have clarified processes such as gap gene kinetics, Hedgehog domains as integrals of signal duration and intensity, Wnt fold-change detection via incoherent feedforward, bi-stability in mutually repressive fate circuits, and thermodynamic cis-regulatory binding. Evolution is framed as assembly, reassembly, and redeployment of sub-circuits, with conserved kernels and clade-specific morphogenetic programs.

Methods

  • Design: comparative review and meta-analysis of published GRNs and mathematical models, not a primary experimental study.
  • Data or sample: published GRNs from sea urchin, Xenopus, C. elegans, zebrafish, Drosophila, vertebrates, haematopoietic systems, and other contexts, drawing on ChIP-chip, perturbation, cis-regulatory, imaging, and modeling studies.
  • Main analysis: structural and functional comparison of sub-circuit topologies and global network hierarchy, alongside discussion of ODE, Boolean, and thermodynamic modeling approaches.

Limitations

  • Stated: many GRNs are compilations from literature or ChIP-chip data that have not been validated by direct perturbation, let alone cis-regulatory analysis; large temporal models often contain many unmeasured parameters and can be circular; bi-stability models frequently assume large Hill coefficients without biochemical evidence; and current GRNs mainly cover either far-upstream patterning or far-downstream differentiation, not continuous top-to-effector linkage.
  • Evident: as a review, the paper presents no new experimental data and uses selected examples to support its synthesis; claims about a finite sub-circuit repertoire and evolutionary modularity remain synthetic hypotheses awaiting broader comparative tests.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nature09645

Cites

90 of 90 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 67 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Developmental gene regulatory networks that control progressive irreversible regulatory processes have considerably greater depth than reversible physiological response circuitry.

    “Some years ago a prescient analysis predicted that in general, developmental GRNs which control progressive irreversible regulatory processes would have considerably greater depth than does reversible physiological response circuitry68, and this turns out to be exactly true.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Rosenfeld, N. & Alon, U. Response delays and the structure of transcription networks. J. Mol. Biol. 329, 645–654 (2003) source

      Not checked in the free run.

  • Findingown data

    All gene regulatory networks considered in the comparative meta-analysis are modular constructs built from a basic repertoire of sub-circuit topologies.

    “they are similar in that all the GRNs considered here are modular constructs of a basic repertoire of sub-circuit topologies (Table 1)”
    Quote in the paperSubstantial claim
  • Premisereasoning

    A circuit's function depends directly on its structure.

    “At root this is because what the circuit can do depends directly on its structure”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The operational significance of a GRN's structure is indicated by the types of sub-circuit it contains.

    “Thus the operational significance of a GRN structure will be indicated by the types of sub-circuit it contains.”
    Quote in the paperSubstantial claim
  • Premisecitation

    GRNs are composed of multiple sub-circuits, each accomplishing a parsed regulatory task.

    “GRNs are composed of multiple sub-circuits, that is, the individual regulatory tasks into which a process can be parsed are each accomplished by a given GRN sub-circuit1–4.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Oliveri, P., Tu, Q. & Davidson, E. H. Global regulatory logic for specification of an embryonic cell lineage. Proc. Natl Acad. Sci. USA 105, 5955–5962 (2008)This paper provides proof of principle that if a developmental GRN is essentially complete, then it provides causal explanations for the biological functions of the process it controls. source

      Not checked in the free run.

    • cites [2] Peter, I. S. & Davidson, E. H. Modularity and design principles in the sea urchin embryo gene regulatory network. FEBS Lett. 583, 3948–3958 (2009)This paper presents the latest comprehensive review of the sea urchin endomesoderm GRN, so far the most extensively validated large scale embryonic GRN, with special emphasis on the topologies of its spatial control sub-circuits. source

      Not checked in the free run.

    • cites [3] Davidson, E. H. The Regulatory Genome. Gene Regulatory Networks in Development and Evolution (Academic Press/Elsevier, 2006)

      Not checked in the free run.

    • cites [4] Alon, U. Network motifs: theory and experimental approaches. Nature Rev. Genet. 8, 450–461 (2007) source

      Not checked in the free run.

  • May combine two claims. 26
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisenone given

    Modular GRN sub-circuits are defined by topology, and topology directly indicates function in life.

    “Modular GRN sub-circuits are defined by their topologies, and the topology of a sub-circuit directly indicates its function in life.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    GRNs give system-level accounts of how development and physiology work in terms of the genomic regulatory code.

    “Gene regulatory networks (GRNs) provide system level explanations of developmental and physiological functions in the terms of the genomic regulatory code.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Mathematical modelling of some GRN sub-circuits has deepened biological understanding of their functions.

    “Mathematical modelling of some types of GRN sub-circuit has deepened biological understanding of the functions they mediate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    GRNs vary in hierarchy and modular sub-circuit types according to developmental function, but share a common sub-circuit repertoire.

    “Depending on their developmental functions, GRNs differ in their degree of hierarchy, and also in the types of modular sub-circuit of which they are composed, although there is a commonly employed sub-circuit repertoire.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    The structural organization of GRNs reflects their roles in life processes and causally illuminates developmental and evolutionary processes.

    “The structural organization of various kinds of GRN reflects their roles in the life process, and causally illuminates both developmental and evolutionary process.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Comparative review shows GRNs can be deeply layered with successive regulatory transactions or shallow with few transactions between initial inputs and terminal effector gene activation.

    “The comparative review below shows that GRNs may be deeply layered, generating successive regulatory transactions, or they may be shallow, in the sense that they mandate few transactions between the initial inputs and the terminal activation of effector genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A given sub-circuit structure implies a given function, and development requires a finite set of regulatory functions.

    “A given sub-circuit structure implies a given function, and in development there is a finite set of regulatory functions required.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a cascade where a gene activates a second downstream gene, significant expression of the second gene occurs long before the first gene product reaches steady state, and the system operates in a forward drive mode relatively insensitive to upstream activator levels.

    “The important insight emerged that in a cascade where a given gene activates a second downstream gene, significant expression of the second gene occurs long before the product of the first gene reaches steady state, and the whole dynamic system operates in a ‘forward drive mode’ relatively insensitive to levels of upstream activators.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Bolouri, H. & Davidson, E. H. Transcriptional regulatory cascades in development: Initial rates, not steady state, determine network kinetics. Proc. Natl Acad. Sci. USA 100, 9371–9376 (2003)This paper models sea urchin regulatory cascade kinetics and demonstrates using measured constants that genes are successively activated long before any of the transcriptional functions attain steady state. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the erythroid/myeloid fate choice system, the specific mutually repressive cis-regulatory interactions are known not to be multimeric and cooperative, and there is no biochemical justification for high Hill coefficients.

    “it was pointed out that the specific, mutually repressive cis-regulatory interactions which were obtained are known not to be multimeric and cooperative, nor is there any other biochemical justification for high Hill coefficients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Chickarmane, V., Enver, T. & Peterson, C. Computational modeling of the hematopoietic erythroid-myeloid switch reveals insights into cooperativity, priming, and irreversibility. PLoS Comput. Biol. 5, e1000268 (2009)This paper presents an alternative computational treatment of lineage choice in a haematopoietic system. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increasing activity of one core repressor causes transcriptional extinction of the alternative choice and irreversible installation of its own positive regulatory state.

    “As the activity of one of the core repressors increases, it causes transcriptional extinction of expression of the alternative choice, and the irreversible installation of its own positive regulatory state”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    High Hill coefficients physically imply cooperativity or additional unknown reactions, but they are customarily inserted despite a lack of direct biological evidence for cooperativity or other justifying physical features.

    “Although Hill coefficients of these magnitudes physically imply cooperativity, or additional (unknown) reactions, they are customarily inserted in the computations despite lack of any direct biological evidence for cooperativity or other physical features that would justify them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Vertebrate embryos use graded inputs, but their developmental systems are cellular and morphogens are diffusible extracellular signal ligands.

    “Vertebrate embryos also use graded inputs, but in this case the developmental systems are cellular, and the ‘morphogens’ are diffusible extracellular signal ligands.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The haematopoietic stem cell sub-circuit consists of three positively active genes, has no cross-regulating repressors, and its three genes are linked by multiple positive auto- and cross-regulatory linkages.

    “This sub-circuit consists of three positively active genes. There are no cross-regulating repressors in this sub-circuit, and the three genes are linked by multiple positive auto- and cross-regulatory linkages.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Pimanda, J. E. et al. Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development. Proc. Natl Acad. Sci. USA 104, 17692–17697 (2007) source

      Not checked in the free run.

    • cites [47] Narula, J., Smith, A. M. & Gottgens, B. and Igoshin, O. A. Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate. PLoS Comput. Biol. 6, e1000771 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    GRNs controlling de novo formation of embryonic territories typically contain many functional sub-circuits governing successive layers and are hierarchical.

    “The GRNs which control the de novo formation of embryonic territories typically include many different functional sub-circuits, which govern successive ‘layers’ of process. They are hierarchical in their overall structure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Sub-circuit topology determines function, and many different regulatory genes can have the same roles.

    “again it is the sub-circuit topology that determines function, and many different regulatory genes can have the same roles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    GRNs controlling later body part and organ development are deep and hierarchical and mostly structured like early embryo GRNs.

    “Like embryonic GRNs, they are deep and hierarchical, and indeed are in most ways structured similarly to the early embryo GRNs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Xenopus mesoderm, C. elegans gut/mesoderm, and zebrafish endoderm and mesoderm GRNs also display deep hierarchical organization.

    “GRNs for specification of mesoderm in Xenopus embryos10, for specification of the gut and mesoderm cell lineages in Caenorhabditis elegans embryos11, and for specification of endoderm and dorsal, anterior and ventral gene expression domains12, and of mesoderm13 in zebrafish, also display deep, hierarchical organizations.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [10] Koide, T., Hayata, T. & Cho, K. W. Y. Xenopus as a model system to study transcriptional regulatory networks. Proc. Natl Acad. Sci. USA 102, 4943–4948 (2005) source

      Not checked in the free run.

    • cites [11] Maduro, M. F. Structure and evolution of the C. elegans embryonic endomesoderm network. Biochim. Biophys. Acta 1789, 250–260 (2009) source

      Not checked in the free run.

    • cites [12] Chan, T.-M. et al. Developmental gene regulatory networks in the zebrafish embryo. Biochim. Biophys. Acta 1789, 279–298 (2009) source

      Not checked in the free run.

    • cites [13] Morley, R. H. et al. A gene regulatory network directed by zebrafish No tail accounts for its roles in mesoderm formation. Proc. Natl Acad. Sci. USA 106, 3829–3834 (2009) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Some of these GRNs are compilations from literature or ChIP-chip data and lack direct perturbation or cis-regulatory validation, but their overall structure is unlikely to be illusory.

    “Some of these GRNs are compilations from the literature or from chromatin immunoprecipitation (ChIP)-chip observations, and have not been validated by direct perturbation analysis, let alone at the cis-regulatory level, but it is unlikely that their overall structure is illusory.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The overall structure of GRNs compiled from literature or ChIP-chip data is unlikely to be illusory.

  • May combine two claims.

    Interpretationreasoning

    The idea that target gene position is determined solely by morphogen concentration is overly simplistic; overall pattern and signal strength response are network properties, not properties of individual cis-regulatory modules.

    “Thus the concept that the position of target gene expression is determined solely by the quantitative value of the ‘morphogen’ is overly simplistic: the overall pattern, and the overall signal strength response mechanism, are actually network properties rather than a property of individual cis-regulatory modules that independently and quantitatively read single gradient values.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The Drosophila dorsal/ventral patterning GRN has extensive cis-regulatory support and is hierarchical, with unusual structure reflecting the syncytial developmental process.

    “The GRN for dorsal/ventral patterning in Drosophila14, which does have extensive cis-regulatory support, is also hierarchical, but its unusual structure reflects the unusual developmental process it controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Stathopoulos, A. & Levine, M. Genomic regulatory networks and animal development. Dev. Cell 9, 449–462 (2005) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The progenitor field is then subdivided into regulatory state domains of subparts, with state locked down at each step.

    “But then the field is subdivided into the regulatory state domains of its subparts, and at each step the state is locked down.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dynamic mathematical analysis of an alternative regulatory architecture for the erythroid/myeloid system predicted that the sub-circuit should include another gene or genes in addition to the antagonistic repressors.

    “Instead an alternative regulatory architecture was considered, the dynamic mathematical analysis of which resulted in the prediction that the sub-circuit should include in addition to the antagonistic repressors another gene or genes operating according to specified network linkages.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Chickarmane, V., Enver, T. & Peterson, C. Computational modeling of the hematopoietic erythroid-myeloid switch reveals insights into cooperativity, priming, and irreversibility. PLoS Comput. Biol. 5, e1000268 (2009)This paper presents an alternative computational treatment of lineage choice in a haematopoietic system. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Gene regulatory networks differ in their global hierarchical organization, and this organization reasonably reflects the biological jobs they perform.

    “but they differ in their global hierarchical organization, which reasonably reflects the biological jobs they execute.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In life and in the model, extrinsic signals switch the haematopoietic stem cell sub-circuit irreversibly into an active state; if one node is inhibited, it remains off.

    “In life and in the model, extrinsic signals switch it irreversibly into an active state; otherwise, if one node is inhibited, it remains off47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Narula, J., Smith, A. M. & Gottgens, B. and Igoshin, O. A. Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate. PLoS Comput. Biol. 6, e1000771 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Recent evidence shows that positions where cis-regulatory modules act depend on combinatorial activator and repressor inputs, and morphogen concentrations alone do not predict target expression domains except sometimes at extreme high concentrations.

    “Much recent evidence, however, shows that the positions where these cis-regulatory modules act depend on combinatorial activator and repressor inputs15–19, and the quantitative values of these ‘morphogens’ alone do not by themselves predict the spatial expression domains of their target genes (except sometimes at the extreme positions where their concentrations are highest).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [15] Hong, J.-W., Hendrix, D. A., Papatsenko, D. & Levine, M. S. How the Dorsal gradient works: insights from postgenome technologies. Proc. Natl Acad. Sci. USA 105, 20072–20076 (2008)This review summarizes work regulatory control of Dorsal target genes expressed spatially along the dorsal/ventral axis of the syncytial Drosophila embryo. source

      Not checked in the free run.

    • cites [16] Liberman, L. M. & Stathopoulos, A. Design flexibility in cis-regulatory control of gene expression: synthetic and comparative evidence. Dev. Biol. 327, 578–589 (2009)This paper presents a novel experimental evidence of cis-regulatory design features in the syncytial dorsal-ventral Drosophila specification system. source

      Not checked in the free run.

    • cites [17] Levine, M. & Davidson, E. H. Gene regulatory networks for development. Proc. Natl Acad. Sci. USA 102, 4936–4942 (2005) source

      Not checked in the free run.

    • cites [18] Ochoa-Espinosa, A., Yu, D., Tsirigos, A., Struffi, P. & Small, S. Anterior-posterior positional information in the absence of a strong Bicoid gradient. Proc. Natl Acad. Sci. USA 106, 3823–3828 (2009)This paper provides experimental evidence that the anterior/posterior specification system of the Drosophila embryo is controlled by a network of gene interactions rather than only by quantitative positional values of Bicoid. source

      Not checked in the free run.

    • cites [19] Liberman, L. M., Teeves, G. T. & Stathopoulos, A. Quantitative imaging of the Dorsal nuclear gradient reveals limitations to threshold-dependent patterning in Drosophila . Proc. Natl Acad. Sci. USA 106, 22317–22322 (2009) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The sea urchin skeletogenic lineage GRN portion contains 24 regulatory genes and several signalling genes, plus downstream differentiation genes.

    “This portion of the network contains 24 regulatory genes and several signalling genes, as well as a sampling of downstream differentiation genes”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Oliveri, P., Tu, Q. & Davidson, E. H. Global regulatory logic for specification of an embryonic cell lineage. Proc. Natl Acad. Sci. USA 105, 5955–5962 (2008)This paper provides proof of principle that if a developmental GRN is essentially complete, then it provides causal explanations for the biological functions of the process it controls. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The oldest gene regulatory network features are certain differentiation gene batteries, which are eumetazoan (cnidarian plus bilaterian) in distribution.

    “in general the oldest GRN features are certain differentiation gene batteries3,88, which are eumetazoan (cnidarian + bilaterian) in distribution.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Davidson, E. H. The Regulatory Genome. Gene Regulatory Networks in Development and Evolution (Academic Press/Elsevier, 2006)

      Not checked in the free run.

    • cites [88] Davidson, E. H. & Erwin, D. H. An integrated view of Precambrian eumetazoan evolution. Cold Spring Harb. Symp. Quant. Biol. 74, 65–80 (2009) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The kinetics of embryonic regulatory interactions are not narrowly determinate, as shown by kinetic sloppiness across temperatures and significant embryo-to-embryo variation in transcription factor concentrations.

    “The kinetics of such embryonic regulatory interactions are not narrowly determinate, as emphasized by the kinetic ‘sloppiness’ of a process which operates successfully at different rates at different temperatures within and between similar species, and in which there is a significant range in the concentrations of many transcription factors embryo to embryo85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Materna, S. C., Nam, J. & Davidson, E. H. High accuracy, high-resolution prevalence measurement for the majority of locally expressed regulatory genes in early sea urchin development. Gene Expr. Patterns 10, 177–184 (2010) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The sub-circuits of which gene regulatory networks are composed change during evolution at different rates, highlighting the linkages belonging to the most conserved sub-circuit in a GRN comparison.

    “Furthermore, the sub-circuits of which GRNs are composed change during evolution at different rates, highlighting the linkages belonging to the most conserved sub-circuit in a GRN comparison.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Development and evolution of the body plan, and execution of physiological responses, devolve causally from the regulatory genome.

    “The processes we have been discussing, development and evolution of the body plan, and execution of physiological responses, devolve causally from the regulatory genome.”
    Quote in the paperNot a substantial claim
30 of 30

  • The paper relies on this without support.

    The body plan and exact mode of development of an animal are encoded in its genome.

    “The body plan of an animal, and hence its exact mode of development, is a property of its species and is thus encoded in the genome.”

  • The paper relies on this without support.

    The sea urchin endomesoderm GRN is the most nearly complete, predictively useful, and validated large-scale developmental GRN currently available.

    “The sea urchin embryo endomesoderm GRN serves as a reference point, as at present it is the most nearly complete, predictively useful, and validated large scale developmental GRN available.”

  • The paper relies on this without support.

    The overall structure of GRNs compiled from literature or ChIP-chip data is unlikely to be illusory.

    “but it is unlikely that their overall structure is illusory.”

  • The paper relies on this without support.

    The binary choice transcriptional apparatus responds to signal intensity.

    “The binary choice transcriptional apparatus responds to signal intensity, so that a low input gives one result and a high input another.”

  • The paper relies on this without support.

    Lineage priming is not seen in embryonic fate choices.

    “is not seen in embryonic fate choices.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Transposable elements provide novel binding sites for the host transcriptional machinery and help create novel regulatory networks.

    “Over the course of evolution, transposable elements provide novel binding sites for the host transcriptional machinery, and thus help create novel regulatory networks (Davidson, 2010; Wray, 2007).”

    From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Davidson, 2010

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Davidson, E. H. The Regulatory Genome. Gene Regulatory Networks in Development and Evolution (Academic Press/Elsevier, 2006)
  2. Davidson, E. H. Genomic Regulatory Systems: Development and Evolution (Academic Press/Elsevier, 2001)

Cited by

Sorted by citations

Authors
Davidson, E. H.
Affiliations
California Institute of Technology (US)
Corresponding author
Davidson, Eric H.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2010-12
Volume
468
Issue
7326
Pages
911-920
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature09645
PMC
PMC3967874
OpenAlex
W2090160722
Semantic Scholar
54675cb92732653a3c050f77a36b7ebacc95f0ca
Cited by
579
References
90
Citations by year
2026: 19 · 2025: 31 · 2024: 31 · 2023: 27 · 2022: 31 · 2021: 34 · 2020: 40 · 2019: 38 · 2018: 32 · 2017: 39 · 2016: 45 · 2015: 39 · 2014: 45 · 2013: 47 · 2012: 52
FWCI
3.56
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (5p01hd037105-20, HD-37105)
  • National Institute of General Medical Sciences (GM 61005, R01GM061005)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01-HD037105, HD37105)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
gene regulatory networks, embryonic development, regulatory proteins, gene expression, network hierarchy, evolutionary developmental biology, cell differentiation
MeSH terms
Animals, Animal Structures, Models, Genetic, Structure-Activity Relationship, Gene Expression Regulation, Developmental, Evolution, Molecular, Pluripotent Stem Cells, Gene Regulatory Networks

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review