Double-Cone Localization and Seasonal Expression Pattern Suggest a Role in Magnetoreception for European Robin Cryptochrome 4
Open accessAbstract
Birds seem to use a light-dependent, radical-pair-based magnetic compass. In vertebrates, cryptochromes are the only class of proteins that form radical pairs upon photo-excitation. Therefore, they are currently the only candidate proteins for light-dependent magnetoreception. Cryptochrome 4 (Cry4) is particularly interesting because it has only been found in vertebrates that use a magnetic compass. However, its structure and localization within the retina has remained unknown. Here, we sequenced night-migratory European robin (Erithacus rubecula) Cry4 from the retina and predicted the currently unresolved structure of the erCry4 protein, which suggests that erCry4 should bind Flavin. We also found that Cry1a, Cry1b, and Cry2 mRNA display robust circadian oscillation patterns, whereas Cry4 shows only a weak circadian oscillation. When we compared the relative mRNA expression levels of the cryptochromes during the spring and autumn migratory seasons relative to the non-migratory seasons in European robins and domestic chickens (Gallus gallus), the Cry4 mRNA expression level in European robin retinae, but not in chicken retinae, is significantly higher during the migratory season compared to the non-migratory seasons. Cry4 protein is specifically expressed in the outer segments of the double cones and long-wavelength single cones in European robins and chickens. A localization of Cry4 in double cones seems to be ideal for light-dependent magnetoreception. Considering all of the data presented here, especially including its localization within the European robin retina, its likely binding of Flavin, and its increased expression during the migratory season in the migratory bird but not in chicken, Cry4 could be the magnetoreceptive protein.
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The double-cone localization of Cry4 and its upregulation during migration periods of migratory birds but not in chickens is further confirmation that the molecule is viable as a magnetoreceptor.
“The double-cone localization of Cry4 as well as the fact that it is upregulated during the migration periods of migratory birds but not in chickens, is further confirmation that the molecule is viable as a magnetoreceptor [106].”
From The future of quantum biology (2018) · cites this paper as [106]
Two studies have offered strong evidence for one of the four cryptochromes, Cry4, playing a role in the avian compass.
“More recently, two studies have offered strong evidence for one of these four cryptochromes, Cry4, playing a role in the avian compass.”
From The future of quantum biology (2018) · cites this paper as [106]
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Self-citationModeling MesoBioNano systems with MBN Studio made easy
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Self-citationTracking the Electron Transfer Cascade in European Robin Cryptochrome 4 Mutants
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Self-citationDouble Cones and the Diverse Connectivity of Photoreceptors and Bipolar Cells in an Avian Retina
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Self-citationCryptochromes: Photochemical and structural insight into magnetoreception
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Upper bound on the biological effects of 50/60 Hz magnetic fields mediated by radical pairs
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Functional evolution of vertebrate sensory receptors
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Self-citationExploring Post-activation Conformational Changes in Pigeon Cryptochrome 4
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Self-citationThe Gain and Loss of Cryptochrome/Photolyase Family Members during Evolution
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Direct Interaction of Avian Cryptochrome 4 with a Cone Specific G-Protein
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One Actor, Multiple Roles: The Performances of Cryptochrome in Drosophila
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Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4
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Self-citationBiological Effects of Space Hypomagnetic Environment on Circadian Rhythm
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A novel isoform of cryptochrome 4 (Cry4b) is expressed in the retina of a night-migratory songbird
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Self-citationModulation of MagR magnetic properties via iron–sulfur cluster binding
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Magnetoreception in birds and its use for long-distance migration
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Self-citationGolesworthy, M. J., Zollitsch, T. M., Luo, J., Selby, D., Jarocha, L. E., Henbest, K. B., Paré-Labrosse, O., Bartölke, R., Schmidt, J., Xu, J., et al. (2023) · The Journal of Chemical Physics · doi:10.1063/5.0166675 · Cited by 29 · see citing works
Self-citationMolSpin—Flexible and extensible general spin dynamics software
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Self-citationBird-Inspired Self-Navigating Artificial Synaptic Compass
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An open quantum system approach to the radical pair mechanism
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Computational Reconstruction and Analysis of Structural Models of Avian Cryptochrome 4
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Self-citationHeyers, D., Musielak, I., Haase, K., Herold, C., Bolte, P., Güntürkün, O., & Mouritsen, H. (2022) · Brain Structure and Function · doi:10.1007/s00429-022-02566-y · Cited by 19 · see citing works
Self-citationAbsorption Spectra of FAD Embedded in Cryptochromes
Nielsen, C., Nørby, M. S., Kongsted, J., & Solov’yov, I. A. (2018) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.8b01528 · Cited by 24 · see citing works
Self-citationRapid Oxidation Following Photoreduction in the Avian Cryptochrome4 Photocycle
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On the optimal relative orientation of radicals in the cryptochrome magnetic compass
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Localisation of cryptochrome 2 in the avian retina
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Self-citationNavigation of migratory songbirds: a quantum magnetic compass sensor
Wong, S. Y., Frederiksen, A., Hanić, M., Schuhmann, F., Grüning, G., Hore, P. J., & Solov’yov, I. A. (2021) · e-Neuroforum · doi:10.1515/nf-2021-0005 · Cited by 21 · see citing works
Self-citationComparative transcriptomic insights into the evolution of vertebrate photoreceptor types
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Cryptochromes in Mammals and Birds: Clock or Magnetic Compass?
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Cryptochromes in mammals: a magnetoreception misconception?
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Lidocaine is a nocebo treatment for trigeminally mediated magnetic orientation in birds
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Self-citationMagnetic‐Field‐Switchable Laser via Optical Pumping of Rubrene
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Species–specific circuitry of double cone photoreceptors in two avian retinas
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Self-citationLight entrainment of retinal biorhythms: cryptochrome 2 as candidate photoreceptor in mammals
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Sjulstok, E., & Solov’yov, I. A. (2020) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.0c00625 · Cited by 17 · see citing works
Self-citationGravell, J., Murton, P. D. F., Pitcher, T. L., Henbest, K. B., Schmidt, J., Buffett, M. M., Moise, G., Gehrckens, A. S., Cubbin, D. R., Štuhec, A., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c14037 · Cited by 16 · see citing works
Self-citationThe expression, localisation and interactome of pigeon CRY2
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Adaptive evolution and loss of a putative magnetoreceptor in passerines
Langebrake, C., Manthey, G., Frederiksen, A., Ramos, J. S. L., Dutheil, J. Y., Chetverikova, R., Solov’yov, I. A., Mouritsen, H., & Liedvogel, M. (2024) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2023.2308 · Cited by 16 · see citing works
Self-citationUnravelling the enigma of bird magnetoreception
Warrant, E. J. (2021) · Nature · doi:10.1038/d41586-021-01596-6 · Cited by 16 · see citing works
Applications of molecular modeling to flavoproteins: Insights and challenges
Sjulstok, E., Solov’yov, I. A., & Freddolino, P. L. (2019) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2019.03.014 · Cited by 14 · see citing works
Self-citationFerrada, P., Rodríguez-Romero, S., Serrano, G., Ostojic, C., Maureira, A., & Zapata, M. (2020) · Applied Sciences · doi:10.3390/app10020531 · Cited by 14 · see citing works
Analysis of zebrafish cryptochrome 2 and 4 expression in UV cone photoreceptors
Balay, S. D., Widen, S. A., & Waskiewicz, A. J. (2020) · Gene Expression Patterns · doi:10.1016/j.gep.2020.119100 · Cited by 13 · see citing works
Prussian blue technique is prone to yield false negative results in magnetoreception research
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Self-citationFrederiksen, A., Langebrake, C., Hanić, M., Manthey, G., Mouritsen, H., Liedvogel, M., & Solov’yov, I. A. (2023) · ACS Omega · doi:10.1021/acsomega.3c02963 · Cited by 12 · see citing works
Self-citationApproaching the Quantum Limit of Energy Resolution in Animal Magnetoreception
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Interplay of Light, Melatonin, and Circadian Genes in Skin Pigmentation Regulation
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Hong, G., Pachter, R., Essen, L., & Ritz, T. (2020) · The Journal of Chemical Physics · doi:10.1063/1.5133019 · Cited by 12 · see citing works
Protein and Solvent Reorganization Drives Radical Pair Stability in Avian Cryptochrome 4a
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Self-citationLaurien, M., Mende, L., Luhrmann, L., Frederiksen, A., Aldag, M., Spiecker, L., Clemmesen, C. M., Solov’yov, I. A., & Gerlach, G. (2024) · Journal of The Royal Society Interface · doi:10.1098/rsif.2024.0035 · Cited by 11 · see citing works
Self-citationKieninger, M., Ventura, O. N., & Kottke, T. (2020) · Biomolecules · doi:10.3390/biom10040573 · Cited by 11 · see citing works
On the optimality of the radical-pair quantum compass
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Atomistic Insights into Cryptochrome Interprotein Interactions
Kimø, S. M., Friis, I., & Solov’yov, I. A. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.06.029 · Cited by 11 · see citing works
Self-citationCryptochrome expression in avian UV cones: revisiting the role of CRY1 as magnetoreceptor
Pinzon-Rodriguez, A., & Muheim, R. (2021) · Scientific Reports · doi:10.1038/s41598-021-92056-8 · Cited by 11 · see citing works
Nuclear polarization effects in cryptochrome-based magnetoreception
Wong, S. Y., Solov’yov, I. A., Hore, P. J., & Kattnig, D. R. (2021) · The Journal of Chemical Physics · doi:10.1063/5.0038947 · Cited by 11 · see citing works
Self-citationDimerization of European Robin Cryptochrome 4a
Hanić, M., Antill, L. M., Gehrckens, A. S., Schmidt, J., Görtemaker, K., Bartölke, R., El‐Baba, T. J., Xu, J., Koch, K., Mouritsen, H., et al. (2023) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.3c01305 · Cited by 10 · see citing works
Self-citationSensitivity enhancement of radical-pair magnetoreceptors as a result of spin decoherence
Luo, J. (2024) · The Journal of Chemical Physics · doi:10.1063/5.0182172 · Cited by 10 · see citing works
Zhang, Y., Zeng, L., Wei, Y., Zhang, M., Pan, W., Sword, G. A., Yang, F., Chen, F., & Wan, G. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.954228 · Cited by 9 · see citing works
Rotov, A. Y., Goriachenkov, A. A., Cherbunin, R. V., Firsov, M. L., Chernetsov, N., & Astakhova, L. A. (2022) · Cells · doi:10.3390/cells11193056 · Cited by 10 · see citing works
Long-Time Oxygen and Superoxide Localization in Arabidopsis thaliana Cryptochrome
Salerno, K. M., Domenico, J., Le, N. Q., Balakrishnan, K., McQuillen, R. J., Stiles, C. D., Solov’yov, I. A., & Martino, C. F. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00325 · Cited by 11 · see citing works
Self-citationFrederiksen, A., Gerhards, L., Reinholdt, P., Kongsted, J., & Solov’yov, I. A. (2024) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.4c02168 · Cited by 10 · see citing works
Self-citationHolub, D., Kubař, T., Mast, T., Elstner, M., & Gillet, N. (2019) · Physical Chemistry Chemical Physics · doi:10.1039/c9cp00694j · Cited by 10 · see citing works
Quantum mechanical spin dynamics of a molecular magnetoreceptor
Lindoy, L. P., Fay, T. P., & Manolopoulos, D. E. (2020) · The Journal of Chemical Physics · doi:10.1063/5.0006411 · Cited by 11 · see citing works
Introducing P ep McConst —A user‐friendly peptide modeler for biophysical applications
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Self-citationImmunohistochemical characterization of bipolar cells in four distantly related avian species
Balaji, V., Haverkamp, S., Seth, P. K., Günther, A., Mendoza, E., Schmidt, J., Herrmann, M., Pfeiffer, L. L., Němec, P., Scharff, C., et al. (2022) · The Journal of Comparative Neurology · doi:10.1002/cne.25443 · Cited by 10 · see citing works
Self-citationYee, C., Bartölke, R., Görtemaker, K., Schmidt, J., Leberecht, B., Mouritsen, H., & Koch, K. (2024) · Scientific Reports · doi:10.1038/s41598-024-79699-z · Cited by 9 · see citing works
Self-citationElectroretinographic study of the magnetic compass in European robins
Astakhova, L. A., Rotov, A. Y., Cherbunin, R. V., Goriachenkov, A. A., Kavokin, K. V., Firsov, M. L., & Chernetsov, N. (2020) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2020.2507 · Cited by 9 · see citing works
The secrets of cryptochromes: photoreceptors, clock proteins, and magnetic sensors
Bartölke, R., Behrmann, H., Görtemaker, K., Yee, C., Xu, J., Behrmann, E., & Koch, K. (2021) · e-Neuroforum · doi:10.1515/nf-2021-0006 · Cited by 9 · see citing works
Self-citationA hybrid compass mechanism combining radical pairs and magnetite crystals
Hore, P. J. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2524093123 · Cited by 8 · see citing works
Magnetoreception in the Retina of the Domestic Pigeon Columbia livia: a Retinographic Search
Rotov, A. Y., Cherbunin, R. V., Kavokin, K. V., Chernetsov, N., Firsov, M. L., & Astakhova, L. A. (2018) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s00220930180600121 · Cited by 8 · see citing works
- Authors
- Günther, A., Einwich, A., Sjulstok, E., Feederle, R., Bolte, P., Koch, K.-W., Solov’yov, I. A., & Mouritsen, H.
- Affiliations
- Carl von Ossietzky Universität Oldenburg (DE)
- University of Southern Denmark (DK)
- Helmholtz Munich (DE)
- Corresponding author
- Mouritsen, Henrik
- ORCID
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 28
- Issue
- 2
- Pages
- 211-223.e4
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2781607775
- Cited by
- 204
- References
- 82
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 12 · 2023: 27 · 2022: 22 · 2021: 32 · 2020: 23 · 2019: 27 · 2018: 14 · 2016: 1
- FWCI
- 12.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- DFG (FOR701, MO 1408/1-2)
- GRK (1885)
- Volkswagen Stiftung
- Air Force Office of Scientific Research (FA9550-14-1-0095)
- Lundbeck Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Geomagnetism and Paleomagnetism Studies
- Keywords
- magnetoreception, European robin, Erithacus rubecula, retina, circadian gene expression, seasonal gene expression, bird migration, radical pair mechanism, flavin binding, photoreceptor outer segments
- MeSH terms
- Animals, Chickens, Gene Expression Regulation, Perception, Seasons, Sequence Analysis, DNA, Retinal Cone Photoreceptor Cells, Songbirds, Animal Migration, Avian Proteins, Cryptochromes, Magnetic Fields
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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.
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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