CRYPTOCHROMES are flavoprotein blue light receptors first identified in plants and subsequently found throughout the biological Kingdom. In plants, cryptochromes are involved in growth and development, response to stress and pathogens, and response to seasonal variations such as the photoperiodic initiation of flowering In insects and mammals, cryptochromes have been most extensively characterized for their role as components of the circadian oscillator. The unique feature of cryptochromes, in contrast with most other cellular receptors present in man, is that they can potentially be activated by external cues such as light and electromagnetic fields.

My research team’s work on cryptochrome has begun with their initial discovery and identification in plants, followed by study of their biological functions (stress response, root and shoot elongation growth, interaction with other plant photoregulatory pathways, phosphorylation effects). More recently our team has characterized light sensitive biochemical reactions of the cryptochromes from both plants and animals and related these primary photoreactions to their signaling function. The team also studies effects of other inputs onto cryptochrome function including effect of cellular metabolites, redox state and oxygen concentration, plant hormones, phosphorylation, and externally applied magnetic fields. The evolutionary origins of cryptochromes from ancestral DNA repair enzymes (photolyases) has been explored, as well as the conserved features among cryptochromes that suggest some common elements in their mechanism of activation across species lines. The team collaborates widely with scientists worldwide comprising expertise in biophysics, structural biology, theoretical physics, animal behaviour, biotechnology and medicine.

• 1.Cryptochromes are implicated in sensitivity to applied magnetic fields. Orientation in birds is based on a magnetic compass mechanism which requires blue/green light. Cryptochrome has been proposed as the magnetic receptor based on its ability to form radical pairs that may be sensitive to applied magnetic fields. We have recently found highly sensitive magnetic effects on plant growth responses and drosophila behavioural responses in blue light to applied fields in the actual geomagnetic range (0.1 to 2x local earth magnetic field). These effects involve cryptochrome. Collaboratively with other teams in the UMR8256(B2A) we have shown that cryptochrome phenotypes are also affected in response to pulsed magnetic fields currently used for medical biotherapeutic applications.

• 2. Structure/Function studies and mechanism of activation of cryptochromes. Experiments with purified proteins and expressing cell cultures show that cryptochromes in vivo respond differently to light than in vitro, and we have related these findings to primary photochemical mechanisms involving flavin reduction and metabolite binding.Furthermore, we have shown that mammalian cryptochromes also respond to light and, collaboratively with other teams of the UMR8256(B2A), we have shown that illumination of mammalian cell cultures has biological effects on cryptochrome-dependent responses in human and mouse cell cultures.

• 3. Cryptochromes are implicated in stress response in animals. Experiments with drosophila and mammalian type cryptochromeshave implicated them in responsivity to oxidative stress and also linked ROS formation and potential signaling roles to cryptochromes in a different cell culture systems.

• 4. Novel roles for cryptochromes in the photoperiodic initiation of Flowering. We show novel roles for plant cryptochromes in the photoperiodic initiation of flowering through interaction with nuclear scaffolding proteins, with a possible link to chromatin architecture and gene silencing functions.

The team has two main axes of research:

• Fundamental studies on structure and function of cryptochromes, mechanisms of activation, downstream signaling mechanisms, and new physiological roles using a variety of experimental systems and approaches in a variety of different organisms (see above). These inlude the mechanism of the response to light, applied electromagnetic fields, and other cellular and environmental factors. A major new direction of the team is to explore novel cryptochrome functions that have potential biomedical implications.

• Applied studies will focusupon using cryptochromes as optogenetic tools.

New biomedical therapies based on activation of cryptochromes either by light or applied electromagnetic fields will be explored in collaboration with team members of the UMR8256 (B2A) who have the necessary biomedical expertise.

In addition applications of cryptochromes to biotechnology and synthetic biology will be developed. The goal is to develop optogenetic operating procedures in cell culture for the cost-effective production of pharmaceuticals and specialty chemicals.

• France:

- André Klarsfeld, IAF, Gif-sur-Yvette

- Francois Rouyer, IAF, Gif-sur-Yvette

- Klaus Brettel, CEA Saclay

- Nicolas Ferré, ICR, Aix-Marseille Université

- Olivier Ouari, ICR, Aix-Marseille Université

• Germany:

- Wolfgang Wiltschko, University of Frankfurt

- Lars Oliver Essen, University of Marburg

- Alfred Batschauer, University of Marburg

- Paul Galland, University of Marburg

- Robert Bittl, Free University Berlin

- Joachim Heberle, Free University Berlin

- Tilmann Kottke, Uni Bielefeld

- Andreas Moeglich, Humboldt University Berlin

- Charlotte Helfrich-Foerster, University of Regensburg

- Eva Wolff, Max Planck Juelich.

• UK:

- Alan Jones, University of Manchester

- Nigel Scrutton, University of Manchester

- Peter Hore, Oxford U.

- John Christie, University of Glasgow

• U.S.A.

- Thorsten Ritz, UC Irvine

• Japan

- Satoru Tokutomi, Osaka prefecture university

- Moritoshi Iino, Osaka City University

- Masahide Terazima, Kyoto University