Sequential actions of β-catenin and Bmp pattern the oral nerve net in Nematostella vectensis
Open accessAbstract
Animal evolution is closely linked to the emergence of the nervous system. At present it is unknown how the basic mechanisms of neural induction and formation of central nervous systems evolved. We addressed this question in Nematostella vectensis , a member of cnidarians, the ancient sister group of bilaterians. We found that β-catenin signalling is crucial for the early induction of the embryonic nervous system. β-Catenin activity at the blastopore induces specific neurogenic genes required for development of the oral nervous system. β-Catenin signalling induces also Bmp signalling, which, at later larval stages, becomes indispensible for the maintenance and asymmetric patterning of the oral nervous system along the primary and secondary (directive) axes. We hypothesize that the consecutive and functionally linked involvement of β-catenin and Bmp signalling in the formation of the cnidarian oral nervous system reflects an ancestral mechanism that evolved before the cnidarian/bilaterian split.
AI snapshot
Written from the paper’s full text.
TL;DR
In *Nematostella vectensis*, β-catenin signalling acts early at the blastopore to induce oral neurogenic genes and neural progenitors, while Bmp signalling later maintains and asymmetrically patterns the oral nervous system. The authors propose this sequential β-catenin→Bmp action reflects an ancestral mechanism for cnidarian oral nerve net development that predates the cnidarian/bilaterian split.
Key findings
- β-Catenin signalling is required early for oral neurogenesis: activating it with DN-GSK3β or GSK3β inhibitors (ALP, BIO, 1-AZA) upregulated *NvSoxB2a*, *NvAshB*, *NvArp3* and *NvBra* at blastula, whereas NvTcf MO or iCRT14 suppressed these genes; iCRT14 also suppressed RFa+, GLWa+ and NvElav1::mOrange+ neurons.
- Bmp signalling acts later and has dual, context-dependent effects: early hBmp2 treatment did not alter early oral TFs or RFa+/GLWa+ neurons, but prolonged hBmp2 to planula reduced early/late oral neurogenic TFs and *NvGlwamide*; Bmp morphants suppressed oral neurogenic genes and neuropeptides and decreased RFa+ and GLWa+ neurons.
- *NvArp6* is asymmetrically expressed along the directive axis on the same side as *NvChordin* and *NvBmp2/4*/*NvBmp5–8*; hBmp2 suppressed *NvArp6*, Bmp double morphants activated it, and NvArp6 morphants almost completely inhibited GLWa+ neurons while RFa+ neurons were unaffected.
- RFamidergic and GLWamidergic neuronal subpopulations correspond to 10% of all neurons at the late planula stage.
Methods
- *N. vectensis* embryos were cultured and analysed by RT-PCR/qPCR, whole-mount in situ hybridization, TnT assays, western blotting, immunostaining and fluorescent/confocal microscopy.
- Functional perturbations included microinjection of mRNAs (DN-GSK3β, DN-β-catenin, NvBmp2/4) and morpholinos against NvSoxB2a, NvAshB, NvArp3, NvArp6, NvBmp2/4, NvBmp5–8 and NvTcf at 250 μM; pharmacological treatments used hBmp2 at 0.1–1 μg ml−1, GSK3β inhibitors ALP/BIO/1-AZA, and iCRT14 at 10 or 50 μM.
- Neural markers included RFamide and GLWamide antibodies, the NvElav1::mOrange transgenic reporter, and phospho-Smad1/5/8 western blotting to monitor Bmp pathway activation.
Limitations
- The paper states that it cannot rule out indirect effects of β-catenin in neuronal cell formation, and that it is unknown how locally activated β-catenin signalling contributes to early lateral neural gene expression at the blastula epithelium.
- The paper notes that GLWa+ neurons depend on additional neurogenic TFs similarly restricted to the oral site, and that whether Wnt/β-catenin regulation of neural patterning is mediated by Bmp activity is left for future studies.
- Evident from the text: conclusions rely heavily on pharmacological inhibitors and morpholino knockdown in one cnidarian species, and the evolutionary interpretation of an ancestral β-catenin/Bmp sequence is a hypothesis rather than a direct phylogenetic test.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 30 cited sources checked · 0 supported · 0 flagged
- Findingown data
NvArp6 is asymmetrically expressed along the secondary (directive) axis.
“we were able to find NvArp6 as the first neurogenic TF being asymmetrically expressed along the secondary (directive) axis”
Quote in the paperSubstantial claim - Findingown data
The polarized expression of early oral neurogenic TFs at the future oral side of the blastula and gastrula is not altered by hBmp2 treatment.
“whereas the polarized expression of early oral neurogenic TFs at the future oral side of the blastula and gastrula was not altered”
Quote in the paperSubstantial claim - Findingown data
Expression of NvChordin is strongly suppressed by augmented Bmp signalling.
“The expression of NvChordin was strongly suppressed by the augmented Bmp signalling”
Quote in the paperSubstantial claim - Findingown data
Bmp signalling at later larval stages is indispensible for the maintenance and asymmetric patterning of the oral nervous system along the primary and secondary (directive) axes.
“which, at later larval stages, becomes indispensible for the maintenance and asymmetric patterning of the oral nervous system along the primary and secondary (directive) axes.”
Quote in the paperSubstantial claim - Findingown data
hBmp2 treatment induces phosphorylation of NvSmad1 in a dose-dependent manner.
“hBmp2 treatment induced the phosphorylation of NvSmad1 in a dose-dependent manner”
Quote in the paperSubstantial claim
- Findingown data
The asymmetry of the endodermal cluster of GLWa+ neurons completely vanished in primary polyps.
“The asymmetry of the endodermal cluster of GLWa+ neurons completely vanished in primary polyps”
Quote in the paperNot a substantial claim - Findingown data
Oral expression of NvBmp2/4, NvBmp5-8 and NvChordin depends on β-catenin signalling.
“The oral expression of NvBmp2/4, NvBmp5–8 and NvChordin was depending on the β-catenin signalling, as the expression was suppressed by iCRT14”
Quote in the paperSubstantial claim - Findingown data
GLWa+ neurons differentiate in the lateral ectoderm and in the oral endoderm of early planulae.
“GLWa+ neurons differentiate in the lateral ectoderm and in the oral endoderm of early planulae”
Quote in the paperSubstantial claim - Findingown data
Development of RFa+ and GLWa+ neurons is not affected by early hBmp2 treatment.
“Consistently, development of the RFa+ and GLWa+ neurons was not affected by the early hBmp2 treatment”
Quote in the paperSubstantial claim - Findingown data
RFamidergic (RFa+) and GLWamidergic (GLWa+) neuronal subpopulations correspond to 10% of all neurons at the late planula stage.
“A quantitative analysis revealed that the RFamidergic (RFa+) and GLWamidergic (GLWa+) neuronal subpopulations correspond to 10% of all neurons at the late planula stage”
Quote in the paperNot a substantial claim - Findingown data
Elav+ neurons form a ring-like sensory cell cluster around the blastopore at the late planula stage.
“Elav+ neurons form a ring-like sensory cell cluster around the blastopore at late planula stage”
Quote in the paperNot a substantial claim - Findingown data
Early oral neurogenic TFs are involved at least partially in the transcriptional control of lateral neural markers from the blastula to planula stage.
“The MO experiments indicated also that these early oral neurogenic TFs are involved at least partially in the transcriptional control of lateral neural markers from the blastula to planula stage”
Quote in the paperSubstantial claim - Findingown data
β-Catenin activity at the blastopore induces specific neurogenic genes required for development of the oral nervous system.
“β-Catenin activity at the blastopore induces specific neurogenic genes required for development of the oral nervous system.”
Quote in the paperSubstantial claim - Findingown data
Elimination of Bmp signalling by co-injection of MOs for NvBmp2/4 and NvBmp5-8 confirms that expression of the early neurogenic TFs is independent of Bmp signalling at the blastula stage.
“Elimination of Bmp signalling by co-injection of MOs for NvBmp2/4 and NvBmp5–8 (ref. 36) confirmed that the expression of the early neurogenic TFs is independent of Bmp signalling at the blastula stage”
Quote in the paperSubstantial claim - Findingown data
NvArp3 is specifically involved in NvElav1 expression at the planula stage.
“which is consistent with the specific involvement of NvArp3 on NvElav1 expression at the planula stage”
Quote in the paperSubstantial claim - Findingown data
Endodermal GLWa+ neurons form a neuronal cluster in an asymmetric manner on one side at the oral region of the planula larvae.
“The endodermal GLWa+ neurons formed a neuronal cluster in an asymmetric manner on one side at the oral region of the planula larvae”
Quote in the paperSubstantial claim - Findingown data
NvArp6 is expressed at the same side of the directive axis as NvChordin, NvBmp2/4 and NvBmp5-8.
“Double WISH analyses indicated that NvArp6 is expressed at the same side of the directive axis as NvChordin (Fig. 8b), and NvBmp2/4 and NvBmp5–8 (ref. 37).”
Quote in the paperSubstantial claim - Findingown data
β-Catenin signalling induces Bmp signalling.
“β-Catenin signalling induces also Bmp signalling”
Quote in the paperSubstantial claim - Findingown data
Extended hBmp2 treatment up to the planula stage reduces expression of early oral NvArp3 and most late oral neurogenic TFs as well as NvGlwamide in a concentration-dependent manner.
“the expression of early oral NvArp3 and most of the late oral neurogenic TFs as well as NvGlwamide were largely reduced by exogenous hBmp2 in a concentration-dependent manner”
Quote in the paperSubstantial claim - Findingown data
NvArp3 forms a synexpression group at the prospective and established blastopore site together with NvSoxB2a and NvAshB during the blastula and gastrula stage.
“We found that NvAtonal-related protein 3 (NvArp3) formed a synexpression group at the prospective and established blastopore site together with the previously described NvSoxB2a and NvAshB1213 during the blastula and gastrula stage”
Quote in the paperSubstantial claim - Findingnone given
Bmp inhibition (which activates NvArp6 but suppresses other oral neuronal TFs) did not result in more and symmetric development of GLWa+ neurons.
“It should be pointed out that Bmp inhibition (which activates NvArp6 but suppresses other oral neuronal TFs) did not result in more and symmetric development of GLWa+ neurons.”
Quote in the paperSubstantial claim - Findingown data
When Bmp signalling was either suppressed or over-activated at gastrula and planula stages, neurogenic TFs and GLWamide neuropeptide became downregulated under both conditions.
“When Bmp signalling was either suppressed or over-activated at gastrula and planula stages, neurogenic TFs and GLWamide neuropeptide became downregulated under both”
Quote in the paperSubstantial claim - Findingown data
At the planula stage, RFa+ and GLWa+ neurons and early and late oral neurogenic TFs (NvArp2, -3, -4, -5, -7, NvAshB, -C, -D) exhibit distinct Bmp sensitivity.
“When we analysed Bmp signalling at the planula stage, we discovered that RFa+ and GLWa+ neurons as well as early and late oral neurogenic TFs (NvArp2, -3, -4, -5, -7, NvAshB, -C, -D) exhibited indeed a distinct Bmp sensitivity.”
Quote in the paperSubstantial claim - Findingown data
NvAshB shows weak Bmp dependency.
“Only for NvAshB this Bmp dependency was weak”
Quote in the paperNot a substantial claim - Findingown data
Bmp signalling at the planula stage asymmetrically induces neurons along the (secondary) directive axis.
“A striking function of Bmp signalling at the planula stage is the asymmetric induction of neurons along the (secondary) directive axis.”
Quote in the paperSubstantial claim - Findingown data
Development of the cnidarian oral nervous system is dependent on early β-catenin- and late Bmp signalling activities.
“Development of the cnidarian oral nervous system is dependent on early β-catenin- and late Bmp signalling activities.”
Quote in the paperSubstantial claim - Findingown data
Bmp signalling is indispensable for development of the oral nervous system in N. vectensis.
“our principal finding that Bmp signalling is indispensable for development of the oral nervous system in N. vectensis”
Quote in the paperSubstantial claim - Findingown data
NvSoxB2a shows no Bmp dependency.
“and it was absent for NvSoxB2a.”
Quote in the paperNot a substantial claim - Findingown data
Bmp signalling had no inhibitory effect on the early induction of oral neuronal genes in N. vectensis.
“When we tested the function of Bmp signalling on the early induction of oral neuronal genes, we could not detect any inhibitory Bmp effect”
Quote in the paperSubstantial claim - Interpretationown data
The β-catenin pathway positively regulates expression of the oral neurogenic TFs NvSoxB2a, NvAshB and NvArp3 at the blastula stage.
“These data therefore indicate that the β-catenin pathway positively regulates expression of the oral neurogenic TFs at the blastula stage.”
Quote in the paperSubstantial claim - Interpretationown data
Early oral neurogenic genes are crucial for the development of the oral nervous system.
“This clearly demonstrated the crucial function of early oral neurogenic genes for the development of the oral nervous system.”
Quote in the paperSubstantial claim - Interpretationreasoning
β-catenin protein that is expressed uniformly in early blastomeres has a role to predispose the blastula epithelium to become neurogenic.
“our findings may suggest that β-catenin protein that is expressed uniformly in early blastomeres has a role to predispose the blastula epithelium to become neurogenic”
Quote in the paperNot a substantial claim - Interpretationown data
NvArp6 activity is specifically required for the differentiation of GLWa+ neurons.
“These data clearly show that NvArp6 activity is specifically required for differentiation of GLWa+ neurons.”
Quote in the paperSubstantial claim - Interpretationown data
β-catenin signalling is crucial for the early induction of the embryonic nervous system in Nematostella vectensis.
“We found that β-catenin signalling is crucial for the early induction of the embryonic nervous system.”
Quote in the paperSubstantial claim - Interpretationown data
NvSoxB2a maintains the expression of the early oral bHLH genes NvAshB and NvArp3 at the planula stage.
“a suppression of NvSoxB2a resulted in the downregulation of NvAshB and NvArp3 (Fig. 2e), indicating that NvSoxB2a maintains the expression of these early oral bHLH genes.”
Quote in the paperSubstantial claim - Interpretationown data
β-catenin signalling is required for the early fate decision of orally and laterally localized neural progenitors giving rise to multiple neuronal cell types in the planula nervous system.
“β-catenin signalling is required for the early fate decision of orally and laterally localized neural progenitors giving rise to multiple neuronal cell types in the planula nervous system.”
Quote in the paperSubstantial claim - Interpretationown data
β-catenin signalling is globally required at an early developmental stage for the expression of oral and lateral neural genes and neurogenic TFs.
“These data indicate that β-catenin signalling is globally required at an early developmental stage for the expression of oral and lateral neural genes and neurogenic TFs.”
Quote in the paperSubstantial claim - Premisecitation
NvElav1 is required at least for ectodermal development of neuropeptides-expressing neurons.
“It was demonstrated that NvElav1 is required at least ectodermal development of neuropeptides-expressing neurons16.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Bier, E. Anti-neural-inhibition: a conserved mechanism for neural induction. Cell 89, 681–684 (1997). source
Not checked in the free run.
- Interpretationown data
The presumptive blastopore region of the blastula represents an early neurogenic field, which gives rise to neuronal populations of the oral (RFa+/GLWa+) and endodermal (NvElav1+) nervous systems.
“the presumptive blastopore region of the blastula represents an early neurogenic field, which gives rise to neuronal populations of the oral (RFa+/GLWa+) and endodermal (NvElav1+) nervous systems.”
Quote in the paperSubstantial claim - Interpretationown data
NvSoxB2a, NvAshB and NvArp3 form a negative gene regulatory circuit at the blastula stage.
“indicating that NvSoxB2a, NvAshB and NvArp3 are not required for the initial steps of most of these genes, but rather form a negative gene regulatory circuit.”
Quote in the paperSubstantial claim - Interpretationreasoning
β-catenin signalling is essential for early cell fate decisions of progenitor cells giving rise to multiple neural cell types.
“Thus, β-catenin signalling is essential for early cell fate decisions of progenitor cells giving rise to multiple neural cell types.”
Quote in the paperSubstantial claim - Interpretationown data
The sequential action of β-catenin and Bmp signalling in N. vectensis reflects the evolutionary emergence of these major signalling axes in the evolution of the nervous system.
“Our data indicate that the sequential action of β-catenin and Bmp signalling in the cnidarian N. vectensis reflects the evolutionary emergence of these major signalling axes in the evolution of the nervous system.”
Quote in the paperNot a substantial claim - Interpretationown data
Bmp signalling has a suppressive function in inducing NvArp6 expression along the primary and directive axes.
“These data clearly indicate that Bmp signalling has a suppressive function in inducing NvArp6 expression along the primary and directive axes.”
Quote in the paperSubstantial claim - Interpretationown data
The localized induction of NvArp6 by Bmp suppression demarcates a specific neurogenic region in the oral nervous system along the directive axis to give rise to the GLWa+ neuronal subdomain.
“Our data also indicate that the localized induction of NvArp6 by Bmp suppression demarcates a specific neurogenic region in the oral nervous system along directive axis to give rise to the GLWa+ neuronal subdomain.”
Quote in the paperSubstantial claim - Interpretationown data
Local expression of NvBmp2/4 and NvBmp5-8 in the gastrula is required for activation of Bmp signalling.
“suggesting that the local expression of NvBmp2/4 and NvBmp5–8 in the gastrula is required for an activation of Bmp signalling”
Quote in the paperSubstantial claim - Interpretationown data
The paper's data support observations in distinct bilaterians showing a function of β-catenin signalling in early neurodevelopment.
“Our data support observations made in distinct bilaterians showing a function of β-catenin signalling in early neurodevelopment”
Quote in the paperNot a substantial claim - Interpretationreasoning
The genetic signature of the cnidarian oral nervous system is shared, at least in part, by that of the bilaterian CNS.
“These findings suggest that the genetic signature of the cnidarian oral nervous system is shared, at least in part, by that of the bilaterian CNS.”
Quote in the paperSubstantial claim - Interpretationreasoning
The cnidarian oral nervous system exhibits important features that are essential for the evolution of the bilaterian CNS.
“we propose that the cnidarian oral nervous system exhibits some important features that are essential for the evolution of the bilaterian CNS (Fig. 9).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Wnt/β-catenin signalling has an additional function in maintaining and/or patterning the cnidarian nervous system.
“This clearly suggests an additional function of Wnt/β-catenin signalling for maintaining and/or patterning the cnidarian nervous system.”
Quote in the paperSubstantial claim - Interpretationreasoning
The β-catenin signalling dependency of neural development at the blastoporal site represents the evolutionarily conserved and ancestral mode of neural development, with a deep root in the common ancestor of cnidarians and bilaterians.
“Instead, the β-catenin signalling dependency of neural development at the blastoporal site appears to represent the evolutionary conserved and ancestral mode of neural development with a deep root in the common ancestor of cnidarians and bilaterians.”
Quote in the paperSubstantial claim - Interpretationown data
The function of these signalling pathways in oral nervous system development is highly reminiscent of their function in the specification of neural cell types in the CNS along bilaterian body axes.
“The function of these signalling pathways in the oral nervous system development is highly reminiscent to their function in the specification of neural cell types in the CNS along bilaterian body axes.”
Quote in the paperSubstantial claim - Interpretationown data
Bmp signalling is an important factor in the development of the oral nervous system.
“Therefore, Bmp signalling is an important factor in the development of the oral nervous system.”
Quote in the paperSubstantial claim - Interpretationcitation
The condensation of neuronal perikaria in the oral nervous system is an anatomical feature related to the formation of a CNS in bilaterians with distinct and functionally specialized neuronal domains (ganglia).
“The condensations of neuronal perikaria in the oral nervous system is an anatomical feature related to the formation of a CNS in bilaterians with distinct and functionally specialized neuronal domains (ganglia)64.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Northcutt, R. G. Evolution of centralized nervous systems: two schools of evolutionary thought. Proc. Natl Acad. Sci. USA 109, (Suppl 1)): 10626–10633 (2012). source
Not checked in the free run.
- Interpretationreasoning
The ancestral mode of neural induction is probably not the Bmp-mediated event described for Xenopus and Drosophila.
“We therefore conclude that the ancestral mode of neural induction is probably not the Bmp-mediated event, which was described for Xenopus and Drosophila21.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Stern, C. D. Neural induction: old problem, new findings, yet more questions. Development 132, 2007–2021 (2005). source
Not checked in the free run.
- Interpretationreasoning
There is evidence for a common set of orthologous neuronal genes expressed in the cnidarian oral nervous system and the bilaterian CNS.
“There is an evidence for a common set of orthologous neuronal genes expressed in the cnidarian oral nervous system and the bilaterian CNS.”
Quote in the paperSubstantial claim - Interpretationreasoning
Wnt/β-catenin regulation of neural patterning might be mediated, at least in part, by Bmp activity.
“the Wnt/β-catenin regulation of neural patterning might be mediated, at least in part, by the Bmp activity.”
Quote in the paperSubstantial claim - Premisecitation
GSK3 inhibitor treatment of gastrulae and planula larvae can cause the formation of multiple polyp heads.
“or even the formation of multiple polyp heads52.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Guder, C. et al. The Wnt code: cnidarians signal the way. Oncogene 25, 7450–7460 (2006). source
Not checked in the free run.
- Premisecitation
Some marker genes for the bilaterian CNS (SoxB1 and Nk2.1) are exclusively expressed in the oral nervous system in N. vectensis.
“some of marker genes for bilaterians CNS (that is, SoxB1 and Nk2.1) are exclusively expressed in the oral nervous system in N. vectensis1236.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12] Magie, C. R., Pang, K. & Martindale, M. Q. Genomic inventory and expression of Sox and Fox genes in the cnidarian Nematostella vectensis. Dev. Genes Evol. 215, 618–630 (2005). source
Not checked in the free run.
- cites [36] Saina, M., Genikhovich, G., Renfer, E. & Technau, U. BMPs and chordin regulate patterning of the directive axis in a sea anemone. Proc. Natl Acad. Sci. USA 106, 18592–18597 (2009). source
Not checked in the free run.
- Interpretationcitation
The asymmetric suppression of Bmp is reminiscent of an evolutionarily conserved Bmp function in the mediolateral patterning of the trunk nervous system in bilaterians.
“This asymmetric suppression of Bmp is reminiscent to an evolutionarily conserved Bmp function in the mediolateral patterning of the trunk nervous system in bilaterians22.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Denes, A. S. et al. Molecular architecture of annelid nerve cord supports common origin of nervous system centralization in bilateria. Cell 129, 277–288 (2007). source
Not checked in the free run.
- Premisecitation
In annelids and hemichordates, Bmp treatments did not inhibit early neurogenic gene expression.
“In annelids22 and in hemichordates24, Bmp treatments did not inhibit early neurogenic gene expression.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [22] Denes, A. S. et al. Molecular architecture of annelid nerve cord supports common origin of nervous system centralization in bilateria. Cell 129, 277–288 (2007). source
Not checked in the free run.
- cites [24] Lowe, C. J. et al. Dorsoventral patterning in hemichordates: insights into early chordate evolution. PLoS Biol. 4, e291 (2006). source
Not checked in the free run.
- Interpretationown data
A balanced level of Bmp signalling is crucial for the development of the oral nervous system.
“Thus, a balanced level of Bmp signalling seems to be crucial for the development of the oral nervous system.”
Quote in the paperSubstantial claim
- May combine two claims. 12
- Classified as probably not a substantial claim. 19
May combine two claims.
Findingown dataIn NvArp6 morphants, there is almost complete inhibition of GLWa+ neurons, whereas RFa+ neurons are not affected.
“In NvArp6 morphants, we found an almost complete inhibition of GLWa+ neurons (Fig. 8f), whereas RFa+ neurons were not affected.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNvArp6 expression is significantly suppressed by hBmp2 treatment and activated in NvBmp2/4/5-8 double morphants.
“NvArp6 expression was significantly suppressed by hBmp2 treatment and activated in NvBmp2/4/5–8 double morphants”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBmp morphants show significant suppression of early and late oral neurogenic genes and of NvRfamide and NvGlwamide, resulting in a decreased number of RFa+ and GLWa+ neurons at the planula stage.
“we also observed a significant suppression of these early and late oral neurogenic genes and of NvRfamide and NvGlwamide (Figs 6f and 7c,d), which resulted in a decreased number of RFa+ and GLWa+ neurons at planula stage”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAugmentation of β-catenin signalling by 1-AZA induces upregulation of NvBmp2/4 and NvBmp5-8, whereas NvChordin expression is inhibited.
“An augmentation of β-catenin signalling by 1-AZA induced upregulation of NvBmp2/4 and NvBmp5–8 expression, whereas NvChordin expression was inhibited”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRFa+ neurons develop in the entire ectoderm and form an elaborated nerve plexus at the oral side, but they do not form an aboral sensory cluster.
“The RFa+ neurons develop in the entire ectoderm and form an elaborated nerve plexus at the oral side, but they did not form an aboral sensory cluster”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningNvArp6-expressing cells and GLWa+ neurons form a distinct asymmetric pattern along the directive axis, which is Bmp dependent.
“NvArp6-expressing cells and GLWa+ neurons form a distinct asymmetric pattern along the directive axis, which is Bmp dependent.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
Findingnone givenExpression of NvBmp2/4, NvBmp5-8 and NvChordin genes is dependent on β-catenin signalling.
“Because the expression of NvBmp2/4, NvBmp5–8 and NvChordin genes is dependent on β-catenin signalling”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenThe oral nervous system is demarcated from other parts of the diffused nervous system and exhibits a distinct condensation of neuronal perikaria with neuronal processes extending to the periphery (tentacles and aboral side).
“The oral nervous system is demarcated from other parts of the diffused nervous system and exhibits a distinct condensation of neuronal perikaria with neuronal processes extending to the periphery (tentacles and aboral side).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationTreatment of gastrulae and planula larvae with GSK3 inhibitors (e.g., ALP or 1-AZA) triggered β-catenin activation and expansion of oral markers including RFa+ neurons.
“Treatment of gastrulae and planula larvae with inhibitors of GSK3 (for example, ALP or 1-AZA) triggered β-catenin activation and the expansion of oral markers including RFa+ neurons6”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Marlow, H. Q., Srivastava, M., Matus, D. Q., Rokhsar, D. & Martindale, M. Q. Anatomy and development of the nervous system of Nematostella vectensis, an anthozoan cnidarian. Dev. Neurobiol. 69, 235–254 (2009). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBmp/Chordin signalling is not necessarily linked to neural induction in bilaterians.
“Therefore, Bmp/Chordin signalling is not necessarily linked to neural induction in bilaterians21.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Stern, C. D. Neural induction: old problem, new findings, yet more questions. Development 132, 2007–2021 (2005). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNvSoxB2a is orthologous to the bilaterian SoxB2 genes.
“has recently been identified as the orthologous gene to the bilaterian SoxB2 genes and was reclassified as NvSoxB2 (ref. 47).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47] Royo, J. L. et al. Transphyletic conservation of developmental regulatory state in animal evolution. Proc. Natl Acad. Sci. USA 108, 14186–14191 (2011). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA neurogenic function of Wnt/β-catenin signalling might be an ancestral bilaterian trait.
“Thus, a neurogenic function of Wnt/β-catenin signalling might be an ancestral bilaterian trait29.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Demilly, A., Steinmetz, P., Gazave, E., Marchand, L. & Vervoort, M. Involvement of the Wnt/beta-catenin pathway in neurectoderm architecture in Platynereis dumerilii. Nat. Commun. 4, 1915 (2013). source
Not checked in the free run.
May combine two claims.
Interpretationown dataNvSoxB2a, NvAshB and NvArp3 have neurogenic function.
“These results clearly indicate that NvSoxB2a, NvAshB and NvArp3 have neurogenic function”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationRFamide and GLWamide serve as specific markers for mature neurons in cnidarians.
“These neuropeptides serve as specific markers for mature neurons in cnidarians8”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Watanabe, H., Fujisawa, T. & Holstein, T. W. Cnidarians and the evolutionary origin of the nervous system. Dev. Growth Differ. 51, 167–183 (2009). source
Not checked in the free run.
May combine two claims.
Interpretationown dataGlobal and localized actions of β-catenin signalling are essential for the neural commitment of early embryonic cells and for the formation of a region with a high neurogenic potential that then develops into the oral nervous system.
“Thus, global and localized actions of β-catenin signalling are essential for the neural commitment of early embryonic cells and for the formation of a region with a high neurogenic potential that then develops into the oral nervous system.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBmp signalling is positively and negatively involved in the development of the oral nervous system.
“These data indicate that Bmp signalling is positively and negatively involved in the development of the oral nervous system.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe oral end of the cnidarian body plan represents the posterior end of the bilaterian AP body axis.
“Since the oral end of the cnidarian body plan is considered to represent the posterior end of the bilaterian AP body axis616263”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [61] Holstein, T. W., Watanabe, H. & Ozbek, S. Signaling pathways and axis formation in the lower metazoa. Curr. Top. Dev. Biol. 97, 137–177 (2011). source
Not checked in the free run.
- cites [62] Holstein, T. W. The Evolution of the Wnt pathway. Cold Spring Harb. Perspect. Biol. 4, a007922 (2012). source
Not checked in the free run.
- cites [63] Croce, J. C. & Holstein, T. W. inWnt Signaling in Development and Disease: Molecular Mechanisms and Biological Functions eds Hoppler S., Moon C. S. 161–176John Wiley & Sons (2014).
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBasic positional information is organized in bilaterians in a Cartesian coordinate system.
“basic positional information, which is organized in bilaterians in a Cartesian coordinate system26”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Niehrs, C. On growth and form: a Cartesian coordinate system of Wnt and BMP signaling specifies bilaterian body axes. Development 137, 845–857 (2010). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral neurogenic TFs (e.g., SoxB and bHLH) and RNA-binding proteins (Elav and Musashi) are present in ctenophore genomes.
“However, several of the ‘neurogenic’ TFs (for example, SoxB and bHLH) and RNA-binding proteins (Elav and Musashi) are present in ctenophore genomes6566.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [65] Ryan, J. F. et al. The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution. Science 342, 1242592 (2013). source
Not checked in the free run.
- cites [66] Moroz, L. L. et al. The ctenophore genome and the evolutionary origins of neural systems. Nature 510, 109–114 (2014). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNvSoxB1 and NvNk2.1 are downregulated in NvChordin and NvBmp2/4 morphants.
“This is reminiscent to the blastoporal regulation of NvSoxB1 and NvNk2.1 that are likewise downregulated in NvChordin and NvBmp2/4 morphants36.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Saina, M., Genikhovich, G., Renfer, E. & Technau, U. BMPs and chordin regulate patterning of the directive axis in a sea anemone. Proc. Natl Acad. Sci. USA 106, 18592–18597 (2009). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMembers of Bmp and β-catenin signalling are highly expressed at the aboral sensory organ and polar fields during ctenophore development.
“In addition, members of Bmp and β-catenin signalling are also highly expressed at this region during development6970.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [69] Pang, K., Ryan, J. F., Mullikin, J. C., Baxevanis, A. D. & Martindale, M. Q. Genomic insights into Wnt signaling in an early diverging metazoan, the ctenophore Mnemiopsis leidyi. Evodevo 1, 10 (2010). source
Not checked in the free run.
- cites [70] Pang, K., Ryan, J. F., Baxevanis, A. D. & Martindale, M. Q. Evolution of the TGF-beta signaling pathway and its potential role in the ctenophore, Mnemiopsis leidyi. PloS ONE 6, e24152 (2011). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAs a control for hBmp2 treatment, 1 μg ml−1 bovine serum albumin (BSA) was applied.
“As a control, 1 μg ml−1 bovine serum albumin (BSA) was applied.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
Interpretationown dataOur data on the development of the oral nervous system in N. vectensis give an insight into how a first step in the evolution of nervous system centralization may have been accomplished.
“our data on the development of the oral nervous system in N. vectensis give an insight how a first step in the evolution of nervous system centralization may have been accomplished.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the ctenophore, SoxB and RFamide are strongly expressed at neuron-enriched body regions, that is, the aboral sensory organ and the polar fields.
“In the ctenophore, SoxB and RFamide are strongly expressed at neuron-enriched body regions, that is, the aboral sensory organ and the polar fields6768.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [67] Jager, M., Queinnec, E., Chiori, R., Le Guyader, H. & Manuel, M. Insights into the early evolution of SOX genes from expression analyses in a Ctenophore. J. Exp. Zool. B Mol. Dev. Evol. 310, 650–667 (2008). source
Not checked in the free run.
- cites [68] Jager, M. et al. New insights on ctenophore neural anatomy: immunofluorescence study in Pleurobrachia pileus (Muller, 1776). J. Exp. Zool. B Mol. Dev. Evol. 316B, 171–187 (2011). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMany neuronal genes are missing in ctenophores, for example, those for the synthesis and transmission of the classical neurotransmitters GABA and acetylcholine.
“Many neuronal genes are missing in ctenophores, for example, those for the synthesis and transmission of the classical neurotransmitters GABA and acetylcholine.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [65] Ryan, J. F. et al. The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution. Science 342, 1242592 (2013). source
Not checked in the free run.
- cites [66] Moroz, L. L. et al. The ctenophore genome and the evolutionary origins of neural systems. Nature 510, 109–114 (2014). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFor semi-quantitative RT-PCR, the level of amplified product was compared in the exponential range of amplification.
“For semi-quantitative RT-PCR, the level of amplified product was compared in the exponential range of amplification.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationNeuropeptides belonging to R[F/Y]amide and [G/V/L]Wamide groups form clusters in the bilaterian CNS.
“The neuropeptides belonging to R[F/Y]amide and [G/V/L]Wamide groups have been shown to form clusters in bilaterian CNS4142.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [41] Tessmar-Raible, K. et al. Conserved sensory-neurosecretory cell types in annelid and fish forebrain: insights into hypothalamus evolution. Cell 129, 1389–1400 (2007). source
Not checked in the free run.
- cites [42] Conzelmann, M. & Jekely, G. Antibodies against conserved amidated neuropeptide epitopes enrich the comparative neurobiology toolbox. Evodevo 3, 23 (2012). source
Not checked in the free run.
May combine two claims.
Interpretationown dataGLWa+ neurons depend on additional neurogenic TFs, which are similarly restricted to the oral site.
“Therefore, GLWa+ neurons depend on additional neurogenic TFs, which are similarly restricted to the oral site.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe translation-blocking MOs were tested using the TnT SP6 quick coupled transcription/translation system.
“The translation-blocking MOs were tested using the TnT SP6 quick coupled transcription/translation system (Promega).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningWnt/β-catenin signalling might be involved in the oral-aboral patterning of the pervasive cnidarian nerve net.
“Wnt/β-catenin signalling might also be involved in the oral–aboral patterning of the pervasive cnidarian nerve net.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationOverlapping expression of NvBmp ligands and its antagonist NvChordin on the same side of the embryo creates a complex gradient of Bmp activity along the primary and directive axes.
“It was proposed that the overlapping expression of the NvBmp ligands and its antagonist NvChordin on the same side of the embryo creates a complex gradient of Bmp activity along the primary and directive axes36.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Saina, M., Genikhovich, G., Renfer, E. & Technau, U. BMPs and chordin regulate patterning of the directive axis in a sea anemone. Proc. Natl Acad. Sci. USA 106, 18592–18597 (2009). source
Not checked in the free run.
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?
RFamide and GLWamide are found in all cnidarians and many bilaterians examined so far.
“Both of them are found in all cnidarians and many bilaterians examined so far [26,28,32–34]”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
GLWamide-positive neurons appear 2-3 days post fertilization and initially appear on one side of the developing pharynx in the planula.
“This population appears 2–3 days post fertilization (dpf), but, unlike the RFamide-positive neurons, the GLWamide-positive neurons initially appear on the one side of the developing pharynx in the planula [28].”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
Manipulation of the Wnt pathway affects the development of oral RFamide and Elav1 neurons, suggesting a conserved role for Wnt signalling in promoting neurogenesis.
“However, in contrast to this idea, recent work showed that manipulation of the Wnt pathway affects the development of oral RFamide and Elav1 neurons [28], suggesting a conserved role for Wnt signalling in promoting neurogenesis.”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
At 4 days post fertilization, RFamide and GLWamide subpopulations make up around 8% of the Elav1-positive neurons.
“It has been reported that at 4 dpf these subpopulations make up around 8% of the Elav1-positive neurons [28].”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
Use of a β-catenin signalling inhibitor severely reduced RFamide, GLWamide and Elav1::mOrange neurons at planula stage, whereas ectopic activation of β-catenin increased the number of these neurons.
“Use of a β-catenin signalling inhibitor resulted in a severe reduction of RFamide, GLWamide and Elav1::mOrange neurons at planula stage, whereas ectopic activation of β-catenin increased the number of these neurons [28].”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
The asymmetric distribution of early GLWamide-positive neurons, together with the RFamide-positive population, depends on BMP signalling along the directive axis.
“Interestingly, the previously mentioned asymmetric distribution of early GLWamide-positive neurons (see above), together with the RFamide-positive population, depends on BMP signalling along the directive axis [28].”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
In Nematostella, BMP signalling appears to have no effect on neuronal differentiation at an early phase, but a proneural function in the later phase of embryonic neurogenesis.
“in Nematostella, BMP signalling appears to have no effect on neuronal differentiation at an early phase, but a proneural function in the later phase of embryonic neurogenesis [28].”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
At early gastrulation, the oral cap is devoid of differentiating neurons, whereas after gastrulation, more neurons-including RFamide and GLWamide neurons-are born in the oral half and in the endoderm.
“At early gastrulation, the oral cap is devoid of differentiating neurons, whereas after gastrulation, more neurons—including some specific subpopulations (RFamide, GLWamide neurons)—are born in the oral half (in and around the pharynx) and in the endoderm [26–28] (figure 3b).”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
Members of the Sox family of genes are involved in the patterning of the neural field and the production of the components of the neural lineage.
“It has been shown that members of the Sox family of genes are involved in the patterning of the neural field and the production of the components of the neural lineage [28,29].”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
Another SoxB2 gene is involved in patterning the oral nervous system.
“In addition to SoxB(2), as mentioned above, another SoxB2 gene is involved in patterning the oral nervous system [28].”
From Evolution of eumetazoan nervous systems: insights from cnidarians (2015) · cites this paper as [28]
The molecular control of neurogenesis in cnidarians is remarkably similar to that in vertebrates: Notch signaling controls the number of neural progenitor cells, soxB and bHLH transcription factor genes regulate their development, and Wnt signaling gradients pattern the nervous system.
“The molecular control of neurogenesis is remarkably similar to that in vertebrates: Notch signalling controls the number of neural progenitor cells, soxB and bHLH transcription factor encoding genes regulate their further development and Wnt signaling gradients are involved in the patterning of the nervous system [99–101].”
From Back to the Basics: Cnidarians Start to Fire (2017) · cites this paper as [101]
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- Authors
- Watanabe, H., Kuhn, A., Fushiki, M., Agata, K., Özbek, S., Fujisawa, T., & Holstein, T. W.
- Affiliations
- Heidelberg University (DE)
- Kyoto University (JP)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Corresponding author
- Watanabe, Hiroshi
- Holstein, Thomas W.
- Venue
- Nature Communications
- Published
- 2014-12-23
- Volume
- 5
- Issue
- 1
- Pages
- 5536-5536
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4284808
- OpenAlex
- W2038221625
- Cited by
- 79
- References
- 70
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 8 · 2022: 9 · 2020: 4 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 12 · 2015: 3
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Alexander von Humboldt-Stiftung
- Toyobo Biotechnology Foundation
- Deutsche Forschungsgemeinschaft (FOR1036, SFB 488)
- Topics
- Physical Sciences › Earth and Planetary Sciences › Paleontology › Marine Invertebrate Physiology and Ecology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
- Keywords
- β-catenin signaling, BMP signaling, Nematostella vectensis, neural induction, blastopore, neurogenic genes, embryonic development
- MeSH terms
- Animals, Biological Evolution, Mouth, Nervous System, Sea Anemones, Signal Transduction, Bone Morphogenetic Proteins, Body Patterning, beta Catenin, Neurogenesis
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