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Cited by 61Hypothalamic control of reproductive hormonesReproductive biology and impacts on aquatic speciesNeurobiology and Insect Physiology Research

Corazonin signaling integrates energy homeostasis and lunar phase to regulate aspects of growth and sexual maturation in Platynereis

Open access
Andreatta, Gabriele, Broyart, Caroline, Borghgraef, Charline, Vadiwala, Karim, Kozin, Vitaly, Polo, Alessandra, Bileck, Andrea, Beets, Isabel +3 more·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1910262116PMC PMC6969523
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Abstract

The molecular mechanisms by which animals integrate external stimuli with internal energy balance to regulate major developmental and reproductive events still remain enigmatic. We investigated this aspect in the marine bristleworm, Platynereis dumerilii , a species where sexual maturation is tightly regulated by both metabolic state and lunar cycle. Our specific focus was on ligands and receptors of the gonadotropin-releasing hormone (GnRH) superfamily. Members of this superfamily are key in triggering sexual maturation in vertebrates but also regulate reproductive processes and energy homeostasis in invertebrates. Here we show that 3 of the 4 gnrh-like ( gnrhl ) preprohormone genes are expressed in specific and distinct neuronal clusters in the Platynereis brain. Moreover, ligand–receptor interaction analyses reveal a single Platynereis corazonin receptor (CrzR) to be activated by CRZ1/GnRHL1, CRZ2/GnRHL2, and GnRHL3 (previously classified as AKH1), whereas 2 AKH-type hormone receptors (GnRHR1/AKHR1 and GnRHR2/AKHR2) respond only to a single ligand (GnRH2/GnRHL4). Crz1/gnrhl1 exhibits a particularly strong up-regulation in sexually mature animals, after feeding, and in specific lunar phases. Homozygous crz1/gnrhl1 knockout animals exhibit a significant delay in maturation, reduced growth, and attenuated regeneration. Through a combination of proteomics and gene expression analysis, we identify enzymes involved in carbohydrate metabolism as transcriptional targets of CRZ1/GnRHL1 signaling. Our data suggest that Platynereis CRZ1/GnRHL1 coordinates glycoprotein turnover and energy homeostasis with growth and sexual maturation, integrating both metabolic and developmental demands with the worm’s monthly cycle.

AI snapshot

Written from the paper’s full text.

TL;DR

Corazonin/GnRH-like signaling in *Platynereis dumerilii* is regulated by sexual maturity, feeding, and lunar phase, and a *crz1/gnrhl1* knockout delays maturation and growth/regeneration without changing food intake. The authors propose CRZ1/GnRHL1 integrates energy homeostasis with developmental and environmental cues by regulating glycoprotein turnover and carbohydrate metabolism.

Key findings

  • *crz1/gnrhl1*, *gnrhl3*, and *gnrh2/gnrhl4* are significantly upregulated in sexually mature male and female worms compared with premature animals; *crz1/gnrhl1* is also significantly upregulated after feeding and during full moon compared with the preceding lunar week.
  • Homozygous *crz1/gnrhl1* mutants show delayed maturation by approximately 5 weeks (n ≥ 213, P < 0.0001), reduced growth at 5 months (n ≥ 75, P < 0.0001), and dampened posterior regeneration in weeks 1, 3, and 4 after amputation (week 2, P = 0.0531; n ≥ 48).
  • Food intake is not significantly affected in *crz1* mutants in two feeding assays (n = 12; n ≥ 25), arguing against an orexigenic explanation for the phenotype.
  • Proteomics and qRT-PCR identify metabolic targets: lysosomal α-mannosidase is downregulated in mutant male heads (1.6-fold enriched in wild-type male proteome; n = 6–7) and in mutant trunks; *tobi*-like α-glucosidases and *pepck* are downregulated, while glycogen synthase is upregulated in mutants (n = 10–13).

Methods

  • The study uses *Platynereis dumerilii* cultures, whole-mount RNA in situ hybridization, qRT-PCR across maturation, lunar phase, and feeding conditions, and a cell culture-based calcium mobilization assay to deorphanize GnRH-superfamily receptors.
  • A *crz1/gnrhl1* knockout strain was generated by TALEN-mediated targeting of exon 2, producing a 1-bp deletion, frameshift, and premature stop codon after 16 amino acids; mutants were compared with wild-type siblings for maturation, growth, regeneration, and feeding.
  • An unbiased proteomic screen (LC-MS/MS, MaxQuant) on heads of sexually mature males and females was combined with qRT-PCR for candidate metabolic enzymes in trunks.

Limitations

  • The paper states that the authors cannot exclude an additional GnRH-like receptor activated by GnRHL3 at lower concentrations, so GnRHL3 remains generically named.
  • The paper states that redundancy among CrzR ligands may mask a strong lunar rhythmicity phenotype in *crz1* mutants, and that the current circalunar spawning paradigm yields broad peaks that might prevent detection of subtle phenotypes.
  • The paper states that it did not attempt to resolve effects on cellular metabolism directly; the text also makes evident that proteomic analysis was limited to heads, with trunk analyses relying on qRT-PCR because reliable trunk proteomics is technically challenging.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.1910262116

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 95 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Whole-mount RNA in situ hybridization identified distinct neuronal clusters expressing 3 of the 4 gnrh-like genes in head samples of mature male and female individuals.

    “These experiments allowed us to identify distinct neuronal clusters expressing 3 of the 4 gnrh-like genes (SI Appendix, Fig. S2 B–D).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Molecular phylogenetic analyses based on amino acid sequence alone do not provide sufficient support for a decisive split of Platynereis GnRH-like preprohormones into CRZ and AKH/GnRH subgroups.

    “molecular phylogenetic analyses based on their amino acid sequence alone do not provide sufficient support for a decisive split into CRZ and AKH/GnRH subgroups (SI Appendix, Figs. S1 and S2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Crz1/gnrhl1 expression is confined to 3 clusters located along the anteroposterior axis in the anterior part of the brain, at the level of the commissure between the anterior and posterior eyes.

    “Crz1/gnrhl1 expression was confined to 3 clusters located along the anteroposterior axis in the anterior part of the brain, at the level of the commissure between the anterior and posterior eyes (SI Appendix, Fig. S2B).”
    Quote in the paperNot a substantial claim
  • Findingcitation

    gnrhl3 is mainly expressed in symmetrical patches in the medial forebrain domains expressing core circadian clock genes.

    “The gnrhl3 gene was mainly expressed in symmetrical patches in the medial forebrain domains expressing core circadian clock genes (8) (SI Appendix, Fig. S2C).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Zantke J., Circadian and circalunar clock interactions in a marine annelid. Cell Rep. 5, 99– 113 (2013). 24075994 PMC3913041 source

      Not checked in the free run.

  • Findingcitation

    Four preprohormones of the GnRH superfamily were identified in Platynereis by transcriptomics, bioinformatics, and mass spectrometry.

    “Four preprohormones of the gnrh superfamily were identified in Platynereis by a combination of transcriptomics, bioinformatics, and mass spectrometry analyses (refs. 53 and 54 and this study).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Conzelmann M., The neuropeptide complement of the marine annelid Platynereis dumerilii. BMC Genomics 14, 906 (2013). 24359412 PMC3890597 source

      Not checked in the free run.

    • cites [54] Williams E. A., Synaptic and peptidergic connectome of a neurosecretory center in the annelid brain. eLife 6, 1– 22 (2017). PMC5747525 29199953 source

      Not checked in the free run.

  • May combine two claims. 33
  • Classified as probably not a substantial claim. 40

  • May combine two claims.

    Findingown data

    crz2/gnrhl2 is detectable in the brain by qRT-PCR but no robust expression pattern could be determined, probably because of low expression levels.

    “Whereas crz2/gnrhl2 is also detectable in the brain by qRT-PCR (see expression analysis in Fig. 2), we could not determine a robust expression pattern, probably because of low expression levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    gnrh2/gnrhl4 localizes in a deep single cluster between the 2 circadian domains as well as in close proximity to the anterior eyes.

    “Finally, gnrh2/gnrhl4 localized in a deep single cluster between the 2 circadian domains as well as in close proximity to the anterior eyes (SI Appendix, Fig. S2D).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    All cnidarian sequences retrieved by searches with either GnRHR-like or VPR/OTR-like receptors clustered together as outgroup to the represented bilaterian GnRHR/VPR/OTR-like receptors.

    “Finally, all cnidarian sequences retrieved by searches with either GnRHR-like or VPR/OTR-like receptors (the most closely related group to all GnRHRs; ref. 58) clustered together as outgroup to the represented bilaterian GnRHR/VPR/OTR-like receptors (Fig. 1A)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Roch G. J., Busby E. R., Sherwood N. M., Evolution of GnRH: Diving deeper. Gen. Comp. Endocrinol. 171, 1– 16 (2011). 21185290 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A GnRH-superfamily receptor with clear orthology to the Corazonin Receptor subfamily (CrzR) was identified and shown to interact with both CRZ1 and CRZ2.

    “A GnRH-superfamily receptor with clear orthology to the Corazonin Receptor subfamily (CrzR) was identified and shown to interact with both CRZ1 and CRZ2 (54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Williams E. A., Synaptic and peptidergic connectome of a neurosecretory center in the annelid brain. eLife 6, 1– 22 (2017). PMC5747525 29199953 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Molecular phylogenetic analyses confirmed that Platynereis CrzR clusters with other CrzRs, while the other 2 newly identified GnRHRs cluster robustly within the AKHR group.

    “Molecular phylogenetic analyses confirmed the clustering of Platynereis CrzR with other CrzRs, while the other 2 newly identified GnRHRs clustered robustly within the AKHR group (Fig. 1A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In crz1−/− worms, both tobi-like 1 and tobi-like 2, as well as pepck, were significantly down-regulated, whereas glycogen synthase was significantly up-regulated.

    “we observed a significant down-regulation of both tobi-like 1 and tobi-like 2, as well as the identified pepck, whereas glycogen synthase was significantly up-regulated (Fig. 4 D–G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This mutation caused a frame shift predicted to produce an aberrant mature peptide, as well as a premature stop codon after 16 amino acids.

    “This mutation caused a frame shift predicted to produce an aberrant mature peptide, as well as a premature stop codon after 16 amino acids (Fig. 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both CrzRa and CrzRb were activated by CRZ1/GnRHL1 and CRZ2/GnRHL2 and, at higher concentration, also by GnRHL3.

    “Both CrzRa and CrzRb were activated by CRZ1/GnRHL1 and CRZ2/GnRHL2 (Fig. 1B and SI Appendix, Fig. S3 C and D; see also ref. 54) and, at higher concentration, also by GnRHL3 (Fig. 1B and SI Appendix, Fig. S3 C and D).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Williams E. A., Synaptic and peptidergic connectome of a neurosecretory center in the annelid brain. eLife 6, 1– 22 (2017). PMC5747525 29199953 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    At 5 mo after fertilization, crz1−/− worms had a significant reduction in total length and number of segments compared to controls.

    “After 3 additional months (5 mo after fertilization), we measured both the total length of the animals and the number of their segments. Now, crz1−/− worms had a significant reduction in both values compared to controls (Fig. 3E and SI Appendix, Fig. S4F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cell culture-based calcium mobilization assay allowed deorphanization of GnRHR1/AKHR1 and GnRHR2/AKHR2 and determined that they were specifically activated by GnRH2/GnRHL4.

    “This assay allowed us to deorphanize the newly discovered GnRHR1/AKHR1 and GnRHR2/AKHR2, and determine that they were specifically activated by GnRH2/GnRHL4 (Fig. 1B and SI Appendix, Fig. S3 A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both gpa and gpb genes exhibited different transcript levels in mature males and female worms, but neither this differential expression nor the expression in premature animals appeared to be changed in crz1−/− animals.

    “Both gpa and gpb genes exhibited different transcript levels in mature males and female worms, but neither this differential expression nor the expression in premature animals appeared to be changed in crz1−/− animals (SI Appendix, Fig. S5 B–E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    crz1/gnrhl1 and crzr transcript levels are lower in the week preceding the nocturnal light stimulus (FM − 1) and higher in the full moon week (FM).

    “the significant difference of crz1/gnrhl1 as well as crzr transcript levels in the week preceding the nocturnal light stimulus (FM − 1; lower expression) and the full moon week itself (FM; higher expression)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The phylogeny suggests that the split in AKHR and ACPR families preceded the diversification of protostomes, implying a secondary loss of ACP signaling in lophotrochozoans.

    “Whereas this phylogeny suggests that the split in AKHR and ACPR families preceded the diversification of protostomes (implying a secondary loss of ACP signaling in lophotrochozoans)”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In flies and humans, changes in expression and activity levels of α-mannosidases have been linked to impairments in insulin signaling and glucose metabolism.

    “In both flies and humans, changes in expression and activity levels of α-mannosidases have been linked to impairments in insulin signaling and glucose metabolism (66–70).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [66] Buch S., Melcher C., Bauer M., Katzenberger J., Pankratz M. J., Opposing effects of dietary protein and sugar regulate a transcriptional target of Drosophila insulin-like peptide signaling. Cell Metab. 7, 321– 332 (2008). 18396138 source

      Not checked in the free run.

    • cites [67] Wolinsky H., Hydrolase activities in the rat aorta. I. Effects of diabetes mellitus and insulin treatment. Circ. Res. 42, 821– 831 (1978). 148980 source

      Not checked in the free run.

    • cites [68] Fushimi H., Shibata M., Tarui S., Glycosidase activities in the liver and kidney of hereditary diabetic mice. J. Biochem. 87, 941– 949 (1980). 7390971 source

      Not checked in the free run.

    • cites [69] Waters P. J., Flynn M. D., Corrall R. J., Pennock C. A., Increases in plasma lysosomal enzymes in type 1 (insulin-dependent) diabetes mellitus: Relationship to diabetic complications and glycaemic control. Diabetologia 35, 991– 995 (1992). 1451959 source

      Not checked in the free run.

    • cites [70] Marchetti P., The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 50, 2486– 2494 (2007). 17906960 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The two apparently conflicting features of the Platynereis GnRH-like system might underline the existence of partially overlapping functions, yet coordinated by distinct neuronal networks.

    “These 2 apparently conflicting features might underline the existence of partially overlapping functions, yet coordinated by distinct neuronal networks.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    These receptor families diverged only after bilaterian origin.

    “consistent with the notion that these receptor families diverged only after bilaterian origin (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Roch G. J., Busby E. R., Sherwood N. M., Evolution of GnRH: Diving deeper. Gen. Comp. Endocrinol. 171, 1– 16 (2011). 21185290 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The phenotype of crz1−/− animals is not due to an orexigenic function of CRZ1/GnRHL1 in Platynereis; instead, CRZ1/GnRHL1 contributes to energy homeostasis.

    “We therefore dismissed the hypothesis that the phenotype of crz1−/− animals was due to an orexigenic function of CRZ1/GnRHL1 in Platynereis, in favor of a contribution of this gene to energy homeostasis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    All bilaterians possess GnRH-like preprohormones.

    “All bilaterians possess GnRH-like preprohormones (12, 13).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Lindemans M., Gonadotropin-releasing hormone and adipokinetic hormone signaling systems share a common evolutionary origin. Front. Endocrinol. (Lausanne) 2, 16 (2011). 22649364 PMC3356000 source

      Not checked in the free run.

    • cites [13] Zandawala M., Tian S., Elphick M. R., The evolution and nomenclature of GnRH-type and corazonin-type neuropeptide signaling systems. Gen. Comp. Endocrinol. 264, 64– 77 (2018). 28622978 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Lysosomal α-mannosidase and plausibly glycoprotein turnover are primary targets of CRZ1/GnRHL1 signaling in Platynereis.

    “Taken together, these analyses identified lysosomal α-mannosidase and plausibly glycoprotein turnover as primary targets of CRZ1/GnRHL1 signaling in Platynereis”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In Drosophila, the ablation of insulin-producing cells of fed flies increased the expression of a lysosomal α-mannosidase in concurrence with a down-regulation of an evolutionary conserved α-glucosidase-target of brain insulin (tobi)-whose overexpression reduces body glycogen.

    “For instance, in Drosophila, the ablation of insulin-producing cells of fed flies increased the expression of a lysosomal α-mannosidase in concurrence with a down-regulation of an evolutionary conserved α-glucosidase—target of brain insulin (tobi) (66)—whose overexpression reduces body glycogen.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Buch S., Melcher C., Bauer M., Katzenberger J., Pankratz M. J., Opposing effects of dietary protein and sugar regulate a transcriptional target of Drosophila insulin-like peptide signaling. Cell Metab. 7, 321– 332 (2008). 18396138 source

      Not checked in the free run.

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

    Premisecitation

    α-mannosidases are a class of ubiquitous enzymes responsible for the hydrolysis of single mannose residues and mainly known for their role in N-linked carbohydrate catabolism during glycoprotein turnover.

    “α-mannosidases are a class of ubiquitous enzymes responsible for the hydrolysis of single mannose residues and mainly known for their role in N-linked carbohydrate catabolism during glycoprotein turnover (65).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Paciotti S., Lysosomal alpha-mannosidase and alpha-mannosidosis. Front. Biosci. (Landmark Ed) 22, 157– 167 (2017). 27814608 source

      Not checked in the free run.

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

    Premisecitation

    A recently suggested unified nomenclature distinguishes 2 main receptor categories: Corazonin receptors (CrzR) and GnRH receptors.

    “Supported by evolutionary arguments, a recently suggested unified nomenclature (13) distinguishes 2 main receptor categories: Corazonin receptors (CrzR) and GnRH receptors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Zandawala M., Tian S., Elphick M. R., The evolution and nomenclature of GnRH-type and corazonin-type neuropeptide signaling systems. Gen. Comp. Endocrinol. 264, 64– 77 (2018). 28622978 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Platynereis CRZ1/GnRHL1 signaling orchestrates growth and sexual maturation according to environmental conditions (nutrient availability and lunar phase), regulating glycoprotein turnover and energy homeostasis.

    “Taken together, our data suggest that Platynereis CRZ1/GnRHL1 signaling orchestrates growth and sexual maturation according to environmental conditions (nutrient availability and lunar phase), regulating glycoprotein turnover and energy homeostasis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In vertebrates, an increase in the activity of GnRH neurons in the hypothalamus is the key event for the precise timing of sexual maturation.

    “In vertebrates, an increase in the activity of GnRH neurons in the hypothalamus is the key event for the precise timing of sexual maturation (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Abreu A. P., Kaiser U. B., Pubertal development and regulation. Lancet Diabetes Endocrinol. 4, 254– 264 (2016). 26852256 PMC5192018 source

      Not checked in the free run.

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

    Premisecitation

    The Octopus peptide was capable to induce LH release in cultured quail pituitary cells.

    “Interestingly, the Octopus peptide was also capable to induce LH release in cultured quail pituitary cells (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Iwakoshi E., Isolation and characterization of a GnRH-like peptide from Octopus vulgaris. Biochem. Biophys. Res. Commun. 291, 1187– 1193 (2002). 11883942 source

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

    Premisecitation

    In mammals, the pulsatile secretion of GnRH is reduced in the nonbreeding (anestrous) season, and the reactivation of the hypothalamic-pituitary-gonadal axis is dictated by a seasonal-dependent increase in kisspeptin expression and a concomitant reduction in Gonadotropin-inhibitory hormone (GnIH) production.

    “In mammals, the pulsatile secretion of GnRH is reduced in the nonbreeding (anestrous) season, and the reactivation of the hypothalamic–pituitary–gonadal axis is dictated by a seasonal-dependent increase in kisspeptin expression and a concomitant reduction in Gonadotropin-inhibitory hormone (GnIH) production (26–28).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Smith J. T., Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: A novel medium for seasonal breeding in the sheep. Endocrinology 149, 5770– 5782 (2008). 18617612 PMC2584593 source

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    • cites [27] Clarke I. J., Smith J. T., Caraty A., Goodman R. L., Lehman M. N., Kisspeptin and seasonality in sheep. Peptides 30, 154– 163 (2009). 18838092 PMC3712824 source

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    • cites [28] Smith J. T., The role of kisspeptin and gonadotropin inhibitory hormone in the seasonal regulation of reproduction in sheep. Domest. Anim. Endocrinol. 43, 75– 84 (2012). 22177698 source

      Not checked in the free run.

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

    Premisecitation

    CRZ signaling coordinates aspects of copulation and fecundity in Drosophila and steroid synthesis in Octopus gonads.

    “For instance, CRZ signaling coordinates aspects of copulation and fecundity in Drosophila (29, 30) and steroid synthesis in Octopus gonads (31).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] Tayler T. D., Pacheco D. A., Hergarden A. C., Murthy M., Anderson D. J., A neuropeptide circuit that coordinates sperm transfer and copulation duration in Drosophila. Proc. Natl. Acad. Sci. U.S.A. 109, 20697– 20702 (2012). 23197833 PMC3528491 source

      Not checked in the free run.

    • cites [30] Bergland A. O., Chae H. S., Kim Y.-J., Tatar M., Fine-scale mapping of natural variation in fly fecundity identifies neuronal domain of expression and function of an aquaporin. PLoS Genet. 8, e1002631 (2012). 22509142 PMC3320613 source

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    • cites [31] Kanda A., Takahashi T., Satake H., Minakata H., Molecular and functional characterization of a novel gonadotropin-releasing-hormone receptor isolated from the common octopus (Octopus vulgaris). Biochem. J. 395, 125– 135 (2006). 16367741 PMC1409690 source

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

    Premisecitation

    Goldfish and zebrafish GnRH2 exhibits an anorexigenic function upon injection.

    “Goldfish and zebrafish GnRH2 exhibits an anorexigenic function upon injection (39, 47, 48).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Matsuda K., Inhibitory effect of chicken gonadotropin-releasing hormone II on food intake in the goldfish, Carassius auratus. Horm. Behav. 54, 83– 89 (2008). 18342861 source

      Not checked in the free run.

    • cites [47] Kang K. S., Gonadotropin-releasing hormone II (GnRH II) mediates the anorexigenic actions of α-melanocyte-stimulating hormone (α-MSH) and corticotropin-releasing hormone (CRH) in goldfish. Peptides 32, 31– 35 (2011). 20955748 source

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    • cites [48] Nishiguchi R., Azuma M., Yokobori E., Uchiyama M., Matsuda K., Gonadotropin-releasing hormone 2 suppresses food intake in the zebrafish, Danio rerio. Front. Endocrinol. (Lausanne) 3, 122 (2012). 23087673 PMC3473230 source

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

    Premisecitation

    In mammals, GnRH release is also regulated by the orexigenic neuropeptide Y (NPY) and kisspeptin, which relays both sex steroid and leptin signaling to GnRH neurons.

    “In mammals, GnRH release is also regulated by the orexigenic neuropeptide Y (NPY) and kisspeptin, which relays both sex steroid and leptin signaling to GnRH neurons (49).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Roa J., Tena-Sempere M., Energy balance and puberty onset: Emerging role of central mTOR signaling. Trends Endocrinol. Metab. 21, 519– 528 (2010). 20554449 source

      Not checked in the free run.

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

    Premisecitation

    GnRH-like peptides affect body mass and feeding in Aplysia, while in Drosophila, both CRZ and AKH regulate carbohydrate and lipid metabolism, as well as feeding and stress response.

    “In addition, GnRH-like peptides affect body mass and feeding in Aplysia (36, 37), while in Drosophila, both CRZ and AKH regulate carbohydrate and lipid metabolism (38–41), as well as feeding (41, 42) and stress response (43, 44).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [36] Tsai P. S., Sun B., Rochester J. R., Wayne N. L., Gonadotropin-releasing hormone-like molecule is not an acute reproductive activator in the gastropod, Aplysia californica. Gen. Comp. Endocrinol. 166, 280– 288 (2010). 19800884 source

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    • cites [37] Johnson J. I., Kavanaugh S. I., Nguyen C., Tsai P.-S., Localization and functional characterization of a novel adipokinetic hormone in the mollusk, Aplysia californica. PLoS One 9, e106014 (2014). 25162698 PMC4146582 source

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    • cites [38] Bharucha K. N., Tarr P., Zipursky S. L., A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis. J. Exp. Biol. 211, 3103– 3110 (2008). 18805809 PMC2714167 source

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    • cites [39] Matsuda K., Inhibitory effect of chicken gonadotropin-releasing hormone II on food intake in the goldfish, Carassius auratus. Horm. Behav. 54, 83– 89 (2008). 18342861 source

      Not checked in the free run.

    • cites [40] Gáliková M., Energy homeostasis control in Drosophila adipokinetic hormone mutants. Genetics 201, 665– 683 (2015). 26275422 PMC4596676 source

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    • cites [41] Kubrak O. I., Lushchak O. V., Zandawala M., Nässel D. R., Systemic corazonin signalling modulates stress responses and metabolism in Drosophila. Open Biol. 6, 160152 (2016). 27810969 PMC5133436 source

      Not checked in the free run.

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

    Premisecitation

    During seasonal changes, nonphotosensitive (photorefractory or reproductively inactive) birds show a reduction in both the number and the size of GnRH immunoreactive cells, a condition reversed in breeding photosensitive animals.

    “During seasonal changes, nonphotosensitive (photorefractory or reproductively inactive) birds show a reduction in both the number and the size of GnRH immunoreactive cells (24), a condition reversed in breeding photosensitive animals (25).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Hahn T. P., Ball G. F., Changes in brain GnRH associated with photorefractoriness in house sparrows (Passer domesticus). Gen. Comp. Endocrinol. 99, 349– 363 (1995). 8536947 source

      Not checked in the free run.

    • cites [25] Deviche P., Saldanha C. J., Silver R., Changes in brain gonadotropin-releasing hormone- and vasoactive intestinal polypeptide-like immunoreactivity accompanying reestablishment of photosensitivity in male dark-eyed juncos (Junco hyemalis). Gen. Comp. Endocrinol. 117, 8– 19 (2000). 10620420 PMC3266068 source

      Not checked in the free run.

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

    Premisecitation

    Gnrh genes are down-regulated in animals exposed to fasting or food restriction.

    “Gnrh genes are down-regulated in animals exposed to fasting or food restriction (45, 46).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Tuziak S. M., Volkoff H., Gonadotrophin-releasing hormone in winter flounder (Pseudopleuronectes americanus): Molecular characterization, distribution and effects of fasting. Gen. Comp. Endocrinol. 184, 9– 21 (2013). 23298570 source

      Not checked in the free run.

    • cites [46] Wang R., Impact of food restriction on the expression of the adiponectin system and genes in the hypothalamic-pituitary-ovarian axis of pre-pubertal ewes. Reprod. Domest. Anim. 51, 657– 664 (2016). 27405252 source

      Not checked in the free run.

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

    Premisecitation

    A high-fat diet increases hypothalamic gnrh expression in prepubescent gilts, where this treatment also advances puberty onset, a result observed also in female mice injected with leptin and in obese girls.

    “In line with this, a high-fat diet increases hypothalamic gnrh expression in prepubescent gilts (50), where this treatment also advances puberty onset, a result observed also in female mice injected with leptin and in obese girls (50–52).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [50] Zhuo Y., Feeding prepubescent gilts a high-fat diet induces molecular changes in the hypothalamus-pituitary-gonadal axis and predicts early timing of puberty. Nutrition 30, 890– 896 (2014). 24985008 source

      Not checked in the free run.

    • cites [51] Chehab F. F., Mounzih K., Lu R., Lim M. E., Early onset of reproductive function in normal female mice treated with leptin. Science 275, 88– 90 (1997). 8974400 source

      Not checked in the free run.

    • cites [52] Biro F. M., Khoury P., Morrison J. A., Influence of obesity on timing of puberty. Int. J. Androl. 29, 272– 277, discussion 286–290 (2006). 16371114 source

      Not checked in the free run.

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

    Premisecitation

    The GnRH receptors also cover the Adipokinetic hormone (AKH) and AKH-CRZ-related peptide (ACP) receptors, diversifications of a single ancestral GnRH receptor likely restricted to arthropods.

    “The GnRH receptors also cover the Adipokinetic hormone (AKH) and AKH-CRZ–related peptide (ACP) receptors, diversifications of a single ancestral GnRH receptor likely restricted to arthropods (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Zandawala M., Tian S., Elphick M. R., The evolution and nomenclature of GnRH-type and corazonin-type neuropeptide signaling systems. Gen. Comp. Endocrinol. 264, 64– 77 (2018). 28622978 source

      Not checked in the free run.

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

    Premisecitation

    GnRH-like systems regulate fecundity in Caenorhabditis elegans, gonadal growth in mollusks, and gamete release (spawning) in Ciona.

    “On the other hand, GnRH-like systems regulate fecundity in Caenorhabditis elegans (33), gonadal growth in mollusks (34), and gamete release (spawning) in Ciona (35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Lindemans M., Adipokinetic hormone signaling through the gonadotropin-releasing hormone receptor modulates egg-laying in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 106, 1642– 1647 (2009). 19164555 PMC2629444 source

      Not checked in the free run.

    • cites [34] Treen N., Mollusc gonadotropin-releasing hormone directly regulates gonadal functions: A primitive endocrine system controlling reproduction. Gen. Comp. Endocrinol. 176, 167– 172 (2012). 22326349 source

      Not checked in the free run.

    • cites [35] Terakado K., Induction of gamete release by gonadotropin-releasing hormone in a protochordate, Ciona intestinalis. Gen. Comp. Endocrinol. 124, 277– 284 (2001). 11742510 source

      Not checked in the free run.

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

    Premisecitation

    The pulsatile secretion of GnRH is crucial for the timing of the monthly reproductive cycle in women.

    “Moreover, the pulsatile secretion of GnRH is crucial for the timing of the monthly reproductive cycle in women (17, 18).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Knobil E., Plant T. M., Wildt L., Belchetz P. E., Marshall G., Control of the rhesus monkey menstrual cycle: Permissive role of hypothalamic gonadotropin-releasing hormone. Science 207, 1371– 1373 (1980). 6766566 source

      Not checked in the free run.

    • cites [18] Barbieri R. L., The endocrinology of the menstrual cycle. Methods Mol. Biol. 1154, 145– 169 (2014). 24782009 source

      Not checked in the free run.

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

    Premisecitation

    This occurs via enhanced release of 2 glycoprotein hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary, promoting steroidogenesis and the maturation of gametes.

    “This occurs via enhanced release of 2 glycoprotein hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary (15), promoting steroidogenesis and the maturation of gametes (16).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Jayes F. C., Britt J. H., Esbenshade K. L., Role of gonadotropin-releasing hormone pulse frequency in differential regulation of gonadotropins in the gilt. Biol. Reprod. 56, 1012– 1019 (1997). 9096885 source

      Not checked in the free run.

    • cites [16] Schally A. V., Gonadotropin-releasing hormone: One polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science 173, 1036– 1038 (1971). 4938639 source

      Not checked in the free run.

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

    Premisecitation

    Circalunar and circasemilunar reproductive rhythms are widespread in marine animals and likely evolutionarily ancient, yet insights about the underlying endocrine effectors are scarce.

    “Circalunar and circasemilunar reproductive rhythms are widespread in marine animals (5) and likely evolutionarily ancient, yet insights about the underlying endocrine effectors are scarce (57, 60, 61).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [5] Raible F., Takekata H., Tessmar-Raible K., An overview of monthly rhythms and clocks. Front. Neurol. 8, 189 (2017). 28553258 PMC5428424 source

      Not checked in the free run.

    • cites [57] Schenk S., Combined transcriptome and proteome profiling reveals specific molecular brain signatures for sex, maturation and circalunar clock phase. eLife 8, e41556 (2019). 30767890 PMC6377233 source

      Not checked in the free run.

    • cites [60] Wang Q., Hong W., Chen S., Zhang Q., Variation with semilunar periodicity of plasma steroid hormone production in the mudskipper Boleophthalmus pectinirostris. Gen. Comp. Endocrinol. 155, 821– 826 (2008). 18068707 source

      Not checked in the free run.

    • cites [61] York P. S., Cummins S. F., Degnan S. M., Woodcroft B. J., Degnan B. M., Marked changes in neuropeptide expression accompany broadcast spawnings in the gastropod Haliotis asinina. Front. Zool. 9, 9 (2012). 22571815 PMC3434067 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisereasoning

    The marine bristleworm Platynereis dumerilii is well suited to tackle the endocrine basis of this integration.

    “The marine bristleworm Platynereis dumerilii is well suited to tackle the endocrine basis of this integration.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [6] Ranzi S., Ricerche sulla biologia sessuale degli Annelidi. Pubbl. Stn. Zool. Napoli 11, 271– 292 (1931).

      Not checked in the free run.

    • cites [7] Hauenschild C., Lunar periodicity. Cold Spring Harb. Symp. Quant. Biol. 25, 491– 497 (1960). 13712278 source

      Not checked in the free run.

    • cites [8] Zantke J., Circadian and circalunar clock interactions in a marine annelid. Cell Rep. 5, 99– 113 (2013). 24075994 PMC3913041 source

      Not checked in the free run.

    • cites [9] Backfisch B., Stable transgenesis in the marine annelid Platynereis dumerilii sheds new light on photoreceptor evolution. Proc. Natl. Acad. Sci. U.S.A. 110, 193– 198 (2013). 23284166 PMC3538230 source

      Not checked in the free run.

    • cites [10] Veedin-Rajan V. B., Fischer R. M., Raible F., Tessmar-Raible K., Conditional and specific cell ablation in the marine annelid Platynereis dumerilii. PLoS One 8, e75811 (2013). 24086637 PMC3782428 source

      Not checked in the free run.

    • cites [11] Bannister S., TALENs mediate efficient and heritable mutation of endogenous genes in the marine annelid Platynereis dumerilii. Genetics 197, 77– 89 (2014). 24653002 PMC4012502 source

      Not checked in the free run.

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

    Premisecitation

    Platynereis is molecularly accessible, and various genetic toolkits allow functional studies.

    “Moreover, this species is molecularly accessible, and various genetic toolkits allow functional studies (9–11).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Backfisch B., Stable transgenesis in the marine annelid Platynereis dumerilii sheds new light on photoreceptor evolution. Proc. Natl. Acad. Sci. U.S.A. 110, 193– 198 (2013). 23284166 PMC3538230 source

      Not checked in the free run.

    • cites [10] Veedin-Rajan V. B., Fischer R. M., Raible F., Tessmar-Raible K., Conditional and specific cell ablation in the marine annelid Platynereis dumerilii. PLoS One 8, e75811 (2013). 24086637 PMC3782428 source

      Not checked in the free run.

    • cites [11] Bannister S., TALENs mediate efficient and heritable mutation of endogenous genes in the marine annelid Platynereis dumerilii. Genetics 197, 77– 89 (2014). 24653002 PMC4012502 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Animals regulate development and reproduction according to environmental cues such as season, temperature, moon phase, and food availability.

    “Animals regulate development and reproduction according to environmental cues such as season, temperature, moon phase, and food availability (1–5).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [1] Colombani J., A nutrient sensor mechanism controls Drosophila growth. Cell 114, 739– 749 (2003). 14505573 source

      Not checked in the free run.

    • cites [2] Schultz T. F., Kay S. A., Circadian clocks in daily and seasonal control of development. Science 301, 326– 328 (2003). 12869749 source

      Not checked in the free run.

    • cites [3] Ebling F. J. P., Barrett P., The regulation of seasonal changes in food intake and body weight. J. Neuroendocrinol. 20, 827– 833 (2008). 18601706 source

      Not checked in the free run.

    • cites [4] Fenelon J. C., Banerjee A., Murphy B. D., Embryonic diapause: Development on hold. Int. J. Dev. Biol. 58, 163– 174 (2014). 25023682 source

      Not checked in the free run.

    • cites [5] Raible F., Takekata H., Tessmar-Raible K., An overview of monthly rhythms and clocks. Front. Neurol. 8, 189 (2017). 28553258 PMC5428424 source

      Not checked in the free run.

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

    Premisecitation

    Worms exhibit a complex life cycle where food availability, circalunar cycle, and season regulate development and sexual maturation.

    “Worms exhibit a complex life cycle where food availability, circalunar cycle, and season regulate development and sexual maturation (6–8).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Ranzi S., Ricerche sulla biologia sessuale degli Annelidi. Pubbl. Stn. Zool. Napoli 11, 271– 292 (1931).

      Not checked in the free run.

    • cites [7] Hauenschild C., Lunar periodicity. Cold Spring Harb. Symp. Quant. Biol. 25, 491– 497 (1960). 13712278 source

      Not checked in the free run.

    • cites [8] Zantke J., Circadian and circalunar clock interactions in a marine annelid. Cell Rep. 5, 99– 113 (2013). 24075994 PMC3913041 source

      Not checked in the free run.

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

    Premisecitation

    In insects, CRZ signaling regulates aspects of metabolism.

    “also in insects, CRZ signaling regulates both aspects of metabolism (40, 80)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Gáliková M., Energy homeostasis control in Drosophila adipokinetic hormone mutants. Genetics 201, 665– 683 (2015). 26275422 PMC4596676 source

      Not checked in the free run.

    • cites [80] Kapan N., Lushchak O. V., Luo J., Nässel D. R., Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin. Cell. Mol. Life Sci. 69, 4051– 4066 (2012). 22828865 PMC11114645 source

      Not checked in the free run.

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

    Premisecitation

    Both AKH peptide in flies and vertebrate glucagon can elicit increased glucose production by both glycogenolysis and gluconeogenesis.

    “Both of these can elicit increased glucose production by both glycogenolysis and gluconeogenesis.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [38] Bharucha K. N., Tarr P., Zipursky S. L., A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis. J. Exp. Biol. 211, 3103– 3110 (2008). 18805809 PMC2714167 source

      Not checked in the free run.

    • cites [66] Buch S., Melcher C., Bauer M., Katzenberger J., Pankratz M. J., Opposing effects of dietary protein and sugar regulate a transcriptional target of Drosophila insulin-like peptide signaling. Cell Metab. 7, 321– 332 (2008). 18396138 source

      Not checked in the free run.

    • cites [77] Christ B., Nath A., Bastian H., Jungermann K., Regulation of the expression of the phosphoenolpyruvate carboxykinase gene in cultured rat hepatocytes by glucagon and insulin. Eur. J. Biochem. 178, 373– 379 (1988). 3061815 source

      Not checked in the free run.

    • cites [78] Lu D., Tamemoto H., Shibata H., Saito I., Takeuchi T., Regulatable production of insulin from primary-cultured hepatocytes: Insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin. Gene Ther. 5, 888– 895 (1998). 9813659 source

      Not checked in the free run.

    • cites [79] Bobe G., Velez J. C., Beitz D. C., Donkin S. S., Glucagon increases hepatic mRNA concentrations of ureagenic and gluconeogenic enzymes in early-lactation dairy cows. J. Dairy Sci. 92, 5092– 5099 (2009). 19762827 source

      Not checked in the free run.

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

    Study design and conductnone given

    Relative expression was calculated using sams as reference gene, and data were normalized to the expression of crz1+/+ (wt) controls.

    “Relative expression was calculated using sams as reference gene, and data were normalized to the expression of crz1+/+ (wt) controls.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    P. dumerilii has emerged as a useful lophotrochozoan reference model that allows cross-comparisons with other bilaterians in aspects such as sensory, hormonal and developmental biology.

    “P. dumerilii has emerged as a useful lophotrochozoan reference model that allows cross-comparisons with other bilaterians in aspects such as sensory, hormonal and developmental biology (71–74).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [71] Arendt D., Tessmar-Raible K., Snyman H., Dorresteijn A. W., Wittbrodt J., Ciliary photoreceptors with a vertebrate-type opsin in an invertebrate brain. Science 306, 869– 871 (2004). 15514158 source

      Not checked in the free run.

    • cites [72] Raible F., Vertebrate-type intron-rich genes in the marine annelid Platynereis dumerilii. Science 310, 1325– 1326 (2005). 16311335 source

      Not checked in the free run.

    • cites [73] Tessmar-Raible K., Conserved sensory-neurosecretory cell types in annelid and fish forebrain: Insights into hypothalamus evolution. Cell 129, 1389– 1400 (2007). 17604726 source

      Not checked in the free run.

    • cites [74] Lauri A., Development of the annelid axochord: Insights into notochord evolution. Science 345, 1365– 1368 (2014). 25214631 source

      Not checked in the free run.

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

    Premisenone given

    The ultimate gamete release is synchronized with the lunar phase.

    “As the ultimate gamete release is synchronized with the lunar phase”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    For qRT-PCR experiments, n = 10 to 13 biological replicates.

    “n = 10 to 13 biological replicates.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The apparent lack of a strong rhythmicity phenotype in crz1−/− worms may be explained by redundancy in the system.

    “A possible explanation for the apparent lack of a strong rhythmicity phenotype is that the system may contain redundancy”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    CRZ1/GnRHL1 impacts Platynereis energy homeostasis, shifting the balance between catabolic and anabolic processes.

    “our data therefore indicate that CRZ1/GnRHL1 impacts on Platynereis energy homeostasis, shifting the balance between catabolic and anabolic processes (Fig. 4H).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In insects, CRZ signaling regulates reproduction (sperm transfer).

    “and reproduction (sperm transfer) (29, 81)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Tayler T. D., Pacheco D. A., Hergarden A. C., Murthy M., Anderson D. J., A neuropeptide circuit that coordinates sperm transfer and copulation duration in Drosophila. Proc. Natl. Acad. Sci. U.S.A. 109, 20697– 20702 (2012). 23197833 PMC3528491 source

      Not checked in the free run.

    • cites [81] Hou Q. L., Corazonin signaling is required in the male for sperm transfer in the oriental fruit fly Bactrocera dorsalis. Front. Physiol. 9, 660 (2018). 29915542 PMC5994612 source

      Not checked in the free run.

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

    Study design and conductnone given

    All animal work was conducted according to Austrian and European guidelines for animal research.

    “All animal work was conducted according to Austrian and European guidelines for animal research.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Platynereis crz1/gnrhl1 helps to adjust energy balance in accordance with the metabolic demand dictated by environmental and developmental cues and thereby contributes to regulate sexual maturation and growth.

    “Our data therefore imply Platynereis crz1/gnrhl1 as a factor that helps to adjust energy balance in accordance with the metabolic demand that is dictated by environmental and developmental cues and thereby contributes to regulate sexual maturation and growth.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In insects, CRZ signaling regulates developmental timing (larval-pupal transition and pupariation).

    “as well as developmental timing (larval–pupal transition and pupariation) (82)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Hou Q. L., A role of corazonin receptor in larval-pupal transition and pupariation in the oriental fruit fly Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). Front. Physiol. 8, 77 (2017). 28261106 PMC5309247

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationcitation

    Down-regulation of lysosomal α-mannosidase leads to unprocessed mannose-rich glycans and related impairment in glycoprotein turnover.

    “insight from other systems strongly suggests that this down-regulation leads to unprocessed mannose-rich glycans and related impairment in glycoprotein turnover”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Experimental overexpression of glycogen synthase causes an increase in glycogen levels in both isolated muscle fibers and mice.

    “whose experimental overexpression has been shown to cause an increase in glycogen levels in both isolated muscle fibers and mice (75, 76).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Azpiazu I., Manchester J., Skurat A. V., Roach P. J., Lawrence J. C. Jr, Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers. Am. J. Physiol. Endocrinol. Metab. 278, E234– E243 (2000). 10662707 source

      Not checked in the free run.

    • cites [76] Manchester J., Skurat A. V., Roach P., Hauschka S. D., Lawrence J. C. Jr, Increased glycogen accumulation in transgenic mice overexpressing glycogen synthase in skeletal muscle. Proc. Natl. Acad. Sci. U.S.A. 93, 10707– 10711 (1996). 8855244 PMC38219 source

      Not checked in the free run.

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

    Study design and conductnone given

    For all qRT-PCR experiments, 4 to 5 trunks were used for single biological replicate.

    “For all qRT-PCR experiments, 4 to 5 trunks were used for single biological replicate.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The dose-response curves arise from at least 4 replicates conducted in at least 2 independent experiments.

    “The dose–response curves arise from at least 4 replicates conducted in at least 2 independent experiments.”
    Quote in the paperNot a substantial claim
58 of 58

  • The paper relies on this without support.

    The integration of multiple environmental stimuli for the regulation of reproduction and growth is still poorly understood.

    “Despite some advances on the molecular mechanisms, the integration of multiple environmental stimuli for the regulation of reproduction and growth is still poorly understood.”

  • The paper relies on this without support.

    Bristleworms metamorphose as the last step of their sexual maturation, characterized by a stop of feeding, development of secondary sexual characters, and final gonadal maturation.

    “Bristleworms metamorphose as the last step of their sexual maturation. This process is characterized by a stop of feeding, the development of secondary sexual characters, and final gonadal maturation.”

  • The paper relies on this without support.

    The timing of metamorphosis is regulated by metabolic cues; worms do not trigger this developmental transition before they attain a minimal size/weight.

    “In addition to the lunar phase, the timing of this process is also regulated by metabolic cues as worms do not trigger this developmental transition before they attain a minimal size/weight.”

  • The paper relies on this without support.

    Metamorphosis requires a sustained energy availability.

    “Given the substantial morphological and physiological changes that occur during this developmental transition under the absence of feeding, metamorphosis requires a sustained energy availability.”

  • The paper relies on this without support.

    Sexually mature P. dumerilii worms commit to an “all in” metabolic performance to reproduce, engaging in an energy-demanding nuptial dance that ultimately leads them to death after spawning.

    “Indeed, sexually mature P. dumerilii worms commit to an “all in” metabolic performance to reproduce, engaging in an energy-demanding nuptial dance that ultimately leads them to death after spawning.”

  • The paper relies on this without support.

    Mature worms do not feed.

    “Finally, mature worms do not feed, further reducing complexity of the analysis.”

  • The paper relies on this without support.

    The 1-bp deletion in crz1/gnrhl1 causes loss of function (knockout).

    “This mutation caused a frame shift predicted to produce an aberrant mature peptide, as well as a premature stop codon after 16 amino acids (Fig. 3A).”

  • The paper relies on this without support.

    P. dumerilii is semelparous and its commitment to reproduction is linked to a fundamental metabolic transition in which worms become anorexic and rely entirely on breakdown of energy stores and recycling to undergo metamorphosis and complete gamete maturation.

    “Due to its semelparous breeding strategy, P. dumerilii is a model system in which energy homeostasis has central relevance. The commitment of worms to reproduction is linked to a fundamental metabolic transition: while worms become anorexic, they rely entirely on the breakdown of energy stores and recycling in order to undergo profound morphological changes (metamorphosis) and complete gamete”

  • The paper relies on this without support.

    The crz1−/− mutant strain's phenotype is due to loss of CRZ1/GnRHL1 function and not to off-target effects.

    “The crz1−/−/gnrhl1−/− strain was generated from a single founder, carrying a 1-bp deletion in the region encoding the CRZ1/GnRHL1 mature peptide. This resulted in a frameshift mutation that abrogated almost the entire mature peptide amino acid sequence and also introduced a premature stop codon after 16 amino acids (Fig. 3A).”
9 of 9

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?

  • In Platynereis dumerilii, homologs of the GnRH-like/Corazonin/AKH supergroup are differentially expressed throughout the worm's circalunar cycle, with the most significant expression changes in the transition from the week prior to the FM stimulus to the FM week.

    “This analysis shows that homologs of the GnRH-like/Corazonin/AKH supergroup are differentially expressed throughout the worm's circalunar cycle with the most significant expression changes in the transition from the week prior to the FM stimulus to the FM week [76].”

    From The Still Dark Side of the Moon: Molecular Mechanisms of Lunar-Controlled Rhythms and Clocks (2020) · cites this paper as [76]

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 3

  1. S. Ranzi, Ricerche sulla biologia sessuale degli Annelidi. Pubbl. Stn. Zool. Napoli 11, 271–292 (1931).
  2. D. K. Hofmann, I. Schiedges, Brain hormone levels and feedback regulation during gametogenesis, metamorphosis and regeneration in Platynereis dumerilii. Front. Zool. 29, 73–79 (1984).
  3. H. Caspers, C. Hauenschild, A. Fischer, “Platynereis dumerilii. Mikroskopische Anatomie, Fortpflanzung, Entwicklung,” in Großes Zoologisches Praktikum Heft 10b (Stuttgart: Gustav Fischer Verlag, 1969).

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Authors
Andreatta, G., Broyart, C., Borghgraef, C., Vadiwala, K., Kozin, V., Polo, A., Bileck, A., Beets, I., Schoofs, L., Gerner, C., & Raible, F.
Affiliations
  • University of Vienna (AT)
  • KU Leuven (BE)
  • Max Perutz Labs, University of Vienna, A-1030 Vienna, Austria;
Corresponding author
  • Andreatta, Gabriele
  • Raible, Florian
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2019-12-16
Volume
117
Issue
2
Pages
1097-1106
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1910262116
PMC
PMC6969523
OpenAlex
W2996337963
Semantic Scholar
9e52b9e7bde0e7783d726f03759bd5489080cf57
Cited by
61
References
87
Citations by year
2026: 5 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 26 · 2021: 9 · 2020: 3 · 2019: 2
FWCI
9.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • Flanders Marine Institute (Flanders Marine Institute) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
  • Austrian Science Fund (I 2972)
  • EC | FP7 | FP7 Ideas: European Research Council (GA 260304)
  • Universität Wien (Research Platform “Rhythms of Life”)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Reproductive biology and impacts on aquatic species
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
Keywords
Platynereis dumerilii, lunar phases, energy homeostasis, sexual maturation, growth regulation, regeneration, carbohydrate metabolism, neuronal gene expression
MeSH terms
Animals, Brain, DNA-Binding Proteins, Homeostasis, Insect Hormones, Invertebrates, Gonadotropin-Releasing Hormone, Neuropeptides, Phylogeny, Polychaeta, Sexual Maturation, Transcription Factors, Signal Transduction, Moon, Receptors, Peptide, Receptors, Neuropeptide, Insect Proteins, Gene Knockdown Techniques

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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 ›

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