Cryptochrome and magnetosensitivity in Drosophila

Many animals use the Earth's magnetic field as a compass and map to aid migration. However, the precise biological origin of animal magnetoreception remains unclear. It is proposed that for an animal to make use of 'geomagnetic' information, there must be something that initially detects the Earth's magnetic field (a 'receptor' or 'sensor') and means by which this information is communicated to critical molecules ('responders') in neurons. Changes triggered in the central nervous system (CNS) result in the animal responding to the magnetic field.

Among the proposed primary magnetosensors is the protein CRYPTOCHROME (CRY). However, neither CRY, nor any other proposed magnetoreceptor, has been conclusively shown to directly produce a magnetically-induced response in the activity of the CNS under real-world conditions. In the laboratory, we have used cellular (electrical activity of central neurons) and whole organism (locomotor behaviour) assays to demonstrate a substantial and reproducible CRY-dependent magnetic field effect in the fruit fly, Drosophila melanogaster. Strikingly, we have shown that this effect persists when just a small fragment of CRY is present. This seriously undermines the established view that only a determined biophysical reaction that requires full-length CRY is necessary and sufficient to make CRY a magnetosensor. Instead, we hypothesize that cells have additional modalities at their disposal to sense magnetic fields. For instance, we have evidence that Flavin Adenine Dinucleotide (FAD), an organic molecule present in all cells, and which CRY binds to, is per se (as a free molecule) receptive to magnetic fields. Therefore, one of our hypotheses is that the magnetic response mediated by the aforementioned small CRY fragment, might reflect an amplification of magnetic sensing by free FAD. The implication is that somehow, free FAD becomes 'coupled' to the small CRY fragment. Alternatively, the 'sensor' could be a different protein able to bind to the CRY fragment. What we think is key to CRY's role, is its ability to bring the 'sensor' near the cellular 'responders', which requires amino acid motifs carried by the small CRY fragment. We will test these hypotheses using genetics and biochemistry to set the scene and then by conducting neurobiological and behavioural investigations. A positive outcome will have a significant impact to the field by establishing a new way of thinking about magnetoreception in animal cells.

The precise biophysical origin of animal magnetoreception remains uncertain. Among the proposed primary magnetoreceptors is the flavoprotein CRYPTOCHROME (CRY), which is thought to provide geomagnetic information via a quantum effect in a light-initiated radical pair (RP) reaction. Our recent work shows that magnetosensitivity, in Drosophila, is maintained when just the CRY C-terminal (CRY-CT) is expressed. This seriously undermines the canonical RP model, which requires full-length CRY, as the main mechanism (not considering magnetite) to sense a magnetic field in vivo. Additionally, we have preliminary evidence that free FAD is able to sense a magnetic field in a cellular model and that CRY-CT amplifies such a mechanism, an avenue that we will pursue further in this application.

On this premise we suggest an alternative scenario to the canonical RP model to be tested in this proposal. Specifically, we suggest that independently of whether CRY may be acting as the primary magnetoreceptor (when full length) or not (as the CRY-CT fragment), identified amino acid motifs in the C-terminal end of the protein are crucial to bring the 'receptor' in to close proximity of the cellular effectors. Published and unpublished evidence suggest that alpha and beta K+ channels may be such effectors, but their role in magnetoreception has never been experimentally demonstrated before. This will be investigated in our proposal. Additionally, as the activity of beta K+ channels depend on cellular redox, we will test the impact of redox on the magnetoresponse. Finally, we will undertake an unbiased approach to identify potential partners of CRY and CRY-CT that might contribute to the magnetic response through additional and unexpected mechanisms.