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Cited by 154Developmental Biology and Gene RegulationGene Regulatory Network AnalysisMarine Invertebrate Physiology and Ecology

Evolutionary plasticity of developmental gene regulatory network architecture

Open access
Hinman, Veronica F., Davidson, Eric H.·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0709994104PMC PMC2148302
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Abstract

Sea stars and sea urchins evolved from a last common ancestor that lived at the end of the Cambrian, approximately half a billion years ago. In a previous comparative study of the gene regulatory networks (GRNs) that embody the genomic program for embryogenesis in these animals, we discovered an almost perfectly conserved five-gene network subcircuit required for endoderm specification. We show here that the GRN structure upstream and downstream of the conserved network kernel has, by contrast, diverged extensively. Mesoderm specification is accomplished quite differently; the Delta–Notch signaling system is used in radically distinct ways; and various regulatory genes have been coopted to different functions. The conservation of the conserved kernel is thus the more remarkable. The results indicate types of network linkage subject to evolutionary change. An emergent theme is that subcircuit design may be preserved even while the identity of genes performing given roles changes because of alteration in their cis -regulatory control systems.

Verified 2026-10-06 · 3 references not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

Comparing endomesoderm gene regulatory networks (GRNs) in a sea star and a sea urchin, the authors find that a conserved five-gene kernel is surrounded by extensive rewiring of upstream and downstream linkages. Delta-Notch signaling, regulatory gene cooption, and mesoderm/endoderm boundary mechanisms differ radically, even though some subcircuit logic is preserved.

Key findings

  • The previously identified five-gene endomesoderm kernel is highly conserved, but outside it “not one of the genes included in Fig. 5 has all of the same regulatory inputs in the two GRNs.”
  • Delta-Notch deployment is radically different: in sea urchins Delta-N signaling specifies mesoderm via gcm and pigment cells, whereas sea star gcm is not expressed in the vegetal plate, gcm transcription is unaffected by Delta MASO, and sea stars form no embryonic pigment cells.
  • A second Delta-N role is conserved: Delta is required for gatae expression and endoderm specification in both species; in sea stars, blocking Delta expands mesodermal gatac and ets1/2 expression and produces excessive migratory blastocoelar cells.
  • tbr is coopted in sea urchins for skeletogenic function, while in sea stars it has the pleisiomorphic endomesodermal role; tbr MASO abolishes from >65% to ≈80% of expression of otxβ1/2, foxa, bra, gatae, tbr itself, and otxα.

Methods

  • Comparative GRN analysis between Asterina miniata (sea star) and Strongylocentrotus purpuratus (sea urchin), whose last common ancestor existed ≈500 million years ago in the Late Cambrian.
  • A. miniata orthologs of delta, ets1/2, and gatac were cloned by low-stringency hybridization and sequenced; spatial expression was assayed by whole-mount in situ hybridization and alkaline phosphatase staining.
  • Gene function was perturbed with morpholino-substituted antisense oligonucleotides (MASOs) targeting Delta, Tbr, Foxa, and Gatae, with quantitative PCR used to measure transcript levels in MASO-treated versus control embryos.

Limitations

  • The paper states that many linkages in the sea star GRN are still missing, including what causes initial mesodermal gatac expression, and notes that some Fig. 5 interactions are dashed because evidence suggests they are indirect.
  • The paper states that gatae up-regulation in the anterior bulb after Delta-N blockade occurs “for reasons not yet known.”
  • Evident from the text: the comparison is limited to two echinoderm species, and several cis-regulatory conclusions are inferred or predicted rather than directly tested in both systems.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.0709994104

Cites

30 of 33 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    In the sea star, Delta is not required for expression of brachyury around the blastopore.

    “Brachyury (bra ), which is expressed normally around the blastopore is similarly unaffected (SI Fig. 6).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    In the sea star, gcm transcription is unaffected by Delta MASO, as shown by WMISH and qPCR.

    “Nor does gcm expression depend on Delta expression as in sea urchins: in the sea star gcm transcription is unaffected in embryos bearing morpholinosubstituted antisense oligonucleotides (MASOs) targeting Delta, as illustrated in Fig. 1 E and F and supported as well by quantitative PCR (qPCR) measurements of transcript levels (data not shown).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    In the sea star, the Delta-expressing cells become the definitive vegetal plate mesoderm, rather than the cells adjacent to it.

    “But the Deltaexpressing cells are what become the definitive vegetal plate mesoderm, rather than the cells adjacent to it, as shown in the later stages portrayed in Fig. 1 B and C .”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    In the sea star Asterina miniata, the delta gene is expressed in the mesodermal progenitors of the central vegetal plate and in scattered ectodermal cells at the blastula stage.

    “The sea star delta gene is expressed within the mesodermal progenitors of the central vegetal plate and scattered in the cells of the ectoderm at the blastula stage (Fig. 1 A ).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    In the sea star, Delta is not required for expression of gatae in the blastopore of late embryos.

    “Expression of gatae in the blastopore of late embryos is unaffected.”
    Quote in the paperSubstantial claim
  • May combine two claims. 24
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Findingown data
    § Results

    In the sea star, Delta is not required for expression of tbrain, otxβ1/2, or otxα.

    “Delta was not required for the expression of several early and broadly endomesodermally expressed transcription factors, i.e., tbrain ( tbr ), otx 𝛃 1 / 2 , or otx 𝛂 (SI Fig. 6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In the sea star, Delta is required for expression of gatae in the gut and for its own expression.

    “Both whole-mount in situ hybridization (WMISH; Fig. 2 C -F ) and quantitative analyses of transcript levels [supporting information (SI) Fig. 6] revealed that Delta is required for expression of gatae in the gut and for its own expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In the sea star, gcm is not expressed in the vegetal plate; instead it shows a spotty pattern of ectodermal expression.

    “AmGcm is not expressed at all within the vegetal plate (Fig. 1 D and E ), instead displaying a spotty pattern of ectodermal expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In the sea star, Delta is not required for quantitative expression of foxa, although the inner-most ring of foxa expression may be reduced.

    “Foxa , which is restricted to the posterior hindgut and blastopore until late gastrula is also unaffected when measured quantitatively (SI Fig. 6), although possibly the inner-most ring of expression of foxa , fated to the more anterior domain of its hindgut expression, is reduced (Fig. 2 C ).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § Results

    Blocking foxa expression does not cause up-regulation of gatac or ets1/2, unlike blocking gatae or Delta-N signaling.

    “But foxa expression can be blocked without causing up-regulation of either gatac or ets1 / 2 (Fig. 3 D and I ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In the sea star, gatac is expressed throughout the central vegetal plate fated to mesoderm, unlike S. purpuratus where expression is restricted to the oral quadrant.

    “In A. miniata , gatac is expressed throughout the central vegetal plate fated to mesoderm (SI Fig. 7), but unlike its orthologue in S. purpuratus its expression is not restricted to the oral quadrant [in the sea urchin embryo the gcmexpressing pigment cell precursors are located in the aboral three-quarters of the mesodermal domain (14)].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data
    § Results

    In the sea star, gatae is normally expressed in the archenteron barrel (future hindgut and midgut) and at very low levels in the mesoderm bulb; in the absence of Delta-N signaling its expression is extinguished in the barrel and dramatically up-regulated in the anterior bulb.

    “Normally in sea star embryos gatae is expressed in the archenteron barrel (future hindgut and midgut) and is expressed at very low levels in the mesoderm bulb (Fig. 2 D ), but in the absence of Delta-N signaling its expression is extinguished in the barrel as we have seen, and, for reasons not yet known, is dramatically up-regulated in the anterior bulb (Fig. 2 E and F , regions marked by * ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Tbr MASO abolishes 65-80% of expression of otxβ1/2, foxa, bra, gatae, tbr itself, and otxα, while control genes not expressed in endomesoderm are unaffected.

    “From > 65% to ≈ 80% of expression of otx 𝛃 1 / 2 , foxa and bra , gatae , tbr itself, and otx 𝛂 is abolished by this treatment, whereas control genes not expressed in endomesoderm at this stage are unaffected.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In Delta MASO sea star embryos, ets1/2 expression is up-regulated, extending throughout the archenteron and at greater than normal intensity.

    “However, in Delta MASO embryos ets1 / 2 expression is also up-regulated, extending throughout the archenteron and at greater than normal intensity (Fig. 3 G ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In Delta-deficient sea star embryos, gatac expression is up-regulated, extends throughout the archenteron, persists during gastrulation, and is more intense than normal.

    “But in Delta-deficient embryos, gatac expression is up- regulated: it extends throughout the archenteron and persists during gastrulation and is more intense than in normal, similarly staged gastrulae (Fig. 3 A vs. B ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    In echinoderms regulatory genes are generally not 2- or 4-fold paralogous, as in mammals, so the process of cis-regulatory changes in input cannot be explained by functional diversification of duplicated genes.

    “We note that in echinoderms regulatory genes are generally not 2- or 4-fold paralogous (31), as in mammals, so the process of cis -regulatory changes in input cannot be explained by functional diversification of duplicated genes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Sea Urchin Genome Sequencing Consortium (2006) Science 314:941-952. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    The tbr gene plays totally different roles in the two systems, and the echinoid use is the cooption while the sea star use is the pleisiomorphic state.

    “As discussed above, tbr plays totally different roles in the two systems, and we know enough from observations in outgroups that it is clear that the echinoid use of this gene is the cooption and the sea star use the pleisiomorphic state.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    This is a surprisingly active evolutionary process, the magnitude of which is partially concealed by its frequently compensatory nature.

    “This is a surprisingly active evolutionary process, the magnitude of which is partially concealed by its frequently compensatory nature.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    The fundamental result is that the genomic regulatory code underlying these similar developmental tasks differs very significantly in the two animals at the cis-regulatory level, but much less so at the circuit design level.

    “The fundamental result of this study, then, is that the genomic regulatory code underlying these similar developmental tasks differs very significantly in the two animals at the cis -regulatory level, but much less so at the circuit design level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    In the sea star the mesoderm/endoderm boundary depends on Foxa repression of gatae in the mesoderm, requiring a Foxa-responsive gatae cis-regulatory module.

    “In the sea star the boundary depends on Foxa repression of gatae in the mesoderm (6), a function that requires a Foxa-responsive gatae cis -regulatory module.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Results

    The sea urchin endomesodermal otxβ1/2 cis-regulatory module lacks a Tbr site and instead another positive regulator interacts with it to drive early expression.

    “Thus, as we show elsewhere (29), the endomesodermal otx 𝛃 1 / 2 cis -regulatory module of the sea urchin indeed lacks a Tbr site and instead another positive regulator interacts with it to drive its early expression; something similar would be predicted for the relevant cis -regulatory module of the delta gene.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Hinman VF, Nguyen A, Davidson EH (2007) Dev Biol , in press.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Discussion

    In sea urchins endoderm cells are prevented from expressing mesoderm genes by foxa repression of gcm, whereas in sea stars endoderm cells are also prevented from expressing mesoderm genes, but by gatae (possibly indirectly) blocking gatac and ets1.

    “In sea urchins endoderm cells are prevented from expressing mesoderm genes by foxa repression of gcm (22, 23), whereas in sea stars endoderm cells are also prevented from expressing mesoderm genes, but not by foxa : instead it is gatae that executes the exclusion function (possibly indirectly), by blocking expression of gatac and ets1 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Oliveri P, Walton KD, Davidson EH, McClay DR (2006) Development (Cambridge, UK ) 133:4173-4181. source

      Not checked in the free run.

    • cites [23] Oliveri P, Davidson EH (2007) Science 315:1510-1511. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § Discussion

    In sea stars Delta-N signaling prevents mesoderm specification in the archenteron barrel, whereas in sea urchins it is required to produce mesoderm specification.

    “in sea stars Delta-N signaling has the effect of preventing mesoderm specification (in the archenteron barrel), whereas in sea urchins it is required to produce mesoderm specification.”
    Quote in the paperSubstantial claim

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

    Interpretationown data
    § Discussion

    The conserved five-gene kernel is shown in red in Fig. 5, and the equally conserved delta to gatae input demonstrated in this work in the sea star has been added.

    “The conserved five-gene kernel discovered earlier is shown in red in Fig. 5, to which we have now added the equally conserved delta to gatae input demonstrated in this work in the sea star.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given
    § Results

    In sea stars, Delta-N signaling functions to limit mesoderm specification, opposite to sea urchins.

    “Not only is Delta-N signaling not used for mesoderm specification in sea stars, but instead it functions oppositely, to limit mesoderm specification.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Results

    In the sea star, foxa represses its own transcription in the mesoderm and represses mesodermal gatae transcription, abolishing expression of both in that territory.

    “But the foxa gene represses its own transcription in the mesoderm and also represses mesodermal gatae transcription, abolishing expression of both in that territory (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Results

    In sea stars, Delta-N signaling potentiates gatae expression in the endoderm, where gatae is not subject to foxa repression; this also occurs in sea urchins in the second phase of Delta-N signaling; in neither does N input into gatae determine the endoderm/mesoderm boundary.

    “In sea stars Delta-N signaling is used to potentiate gatae expression in the endoderm, where this gene is not subject to foxa repression. It does this in sea urchins, too, in the second phase of Delta-N signaling, and in neither does N input into gatae determine the endoderm/mesoderm boundary.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    In sea urchin, gatae runs in both mesoderm and endoderm almost up to gastrulation, so it can provide input into mesoderm genes and does so to gatac, a role impossible in sea star.

    “In the sea urchin gatae runs in both the mesoderm and endoderm almost up to gastrulation. The consequence is that this gene can be used to provide input into mesoderm genes in sea urchin and does so to gatac , a role that would be impossible in the sea star.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Results

    In sea stars, the origin of the mesoderm/endoderm boundary is ultimately repression of gatae in the mesoderm by foxa, whereas in sea urchins it is the initial phase of Delta-N signaling.

    “In other words, the origin of the mesoderm/endoderm boundary in sea stars is ultimately the repression of gatae in the mesoderm by foxa , whereas in sea urchins it is the initial phase of Delta-N signaling.”
    Quote in the paperSubstantial claim
24 of 24

  • The paper relies on this without support.

    Embryonic pigment cells are not formed at all in sea stars as they are in euechinoids.

    “Embryonic pigment cells are not formed at all in sea stars as they are in euechinoids.”

  • The paper relies on this without support.

    The sea star embryo lacks micromeres and makes no embryonic skeleton.

    “The sea star embryo not only lacks micromeres but also makes no embryonic skeleton.”

  • The paper relies on this without support.

    None of the other five echinoderm classes possesses a skeletogenic micromere lineage.

    “Because none of the other five echinoderm classes possesses a skeletogenic micromere lineage, the sea star represents in this respect the pleisiomorphic state, and the sea urchin represents the derived state.”

  • The paper relies on this without support.

    Sea stars produce vegetal plate mesoderm that is topologically central to the surrounding ring of cells which become endoderm.

    “Sea stars also produce vegetal plate mesoderm, that just as in sea urchins, is topologically central to the surrounding ring of cells, which become endoderm, but they must use a different mesodermal specification mechanism.”

  • The paper relies on this without support.

    In sea urchins, the cells of the vegetal plate that are exposed to the initial Delta-N signal become mesoderm, and the peripheral cells that are not become endoderm.

    “In sea urchins the cells of the vegetal plate that are exposed to the initial Delta-N signal become mesoderm, and the peripheral cells that are not become endoderm.”

  • The paper relies on this without support.

    In S. purpuratus, foxa has no input to gatae, which is expressed in both until just before gut invagination.

    “It has no input to gatae , which is expressed in both until just before gut invagination.”
6 of 6

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?

  • A comparison between sea urchin and sea star endomesodermal GRNs revealed an extremely conserved 5-gene subcircuit surrounded by linkages none of which had survived the half billion years since divergence without change.

    “Sometimes the contrast between the conserved and non-conserved parts of a given GRN is quite dramatic, as in a comparison between sea urchin and sea star endomesodermal GRNs that revealed an extremely conserved, 5-gene subcircuit, surrounded by linkages not one of which had survived the half billion years since divergence without change (Hinman and Davidson, 2007).”

    From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Hinman and Davidson, 2007

    The introduction describes a conserved five-gene subcircuit in sea star and sea urchin GRNs and dates their common ancestor to about 500 million years ago. The Discussion reports extensive rewiring outside the subcircuit, but the Results explicitly identify a conserved Delta-to-gatae regulatory linkage. Thus, the claim that not one surrounding linkage survived unchanged is too absolute. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • tbr provides an explicit case of cooption because it is expressed in endomesoderm in other echinoderms including sea stars, where it is obligatory for endomesoderm specification, whereas in echinoids it is expressed only in the skeletogenic micromere lineage.

    “tbr provides an explicit case of cooption, because this gene is expressed in endomesoderm in other echinoderms, including sea stars (20, 21), where it is obligatory for endomesoderm specification (21); in echinoids, tbr is expressed only in the skeletogenic micromere lineage.”

    From Transfer of a large gene regulatory apparatus to a new developmental address in echinoid evolution (2008) · cites this paper as [21]

  • Certain remarkably conserved regulatory sub-circuits located near the top of developmental GRN hierarchy may serve to lock down developmental processes specific to given phyla or classes (GRN kernels).

    “Certain remarkably conserved regulatory sub-circuits that are located near the top of developmental GRN hierarchy may serve to lock down developmental process specific to given phyla or classes (GRN kernels)86–91.”

    From Emerging properties of animal gene regulatory networks (2010) · cites this paper as [90]

Cites

Flagged first, then by citations

1 of the 34 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. YK Maruyama Zool Sci 17, 383–387 (2000).
  2. VF Hinman, A Nguyen, EH Davidson Dev Biol, in press. (2007).

Cited by

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Related

Authors
Hinman, V. F., & Davidson, E. H.
Affiliations
  • Carnegie Mellon University (US)
  • California Institute of Technology (US)
Corresponding author
Davidson, Eric H.
ORCID
Hinman, Veronica F.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2007-12-04
Volume
104
Issue
49
Pages
19404-19409
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0709994104
PMC
PMC2148302
OpenAlex
W2167934696
Cited by
154
References
34
Citations by year
2026: 5 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 4 · 2017: 14 · 2016: 6 · 2015: 9 · 2014: 11 · 2013: 7 · 2012: 17
FWCI
4.76
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
National Science Foundation (0641398)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Physical Sciences › Earth and Planetary Sciences › Paleontology › Marine Invertebrate Physiology and Ecology
Keywords
gene regulatory networks, evolutionary plasticity, sea stars, sea urchins, endoderm specification, mesoderm specification, Delta-Notch signaling, embryonic development, evolutionary developmental biology
MeSH terms
Animals, Endoderm, Mesoderm, Sea Urchins, Starfish, Signal Transduction, Evolution, Molecular, T-Box Domain Proteins, Receptors, Notch, Gene Regulatory Networks

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