Team
COBIF
Team manager: Cau Elise
Circadian organization is a ubiquitous feature of biological functions from transcription to behavior. Dysregulation of the circadian system either genetic or caused by shift work is associated to a wide range of diseases such as sleep disorders, metabolic syndromes, cardiovascular diseases, affective disorders and tumorigenesis. At the root of the circadian system, a transcriptional/translational loop (referred to as the molecular clock) is operating in every cell. Circadian rhythms have been extensively studied in nocturnal species (mouse, rat) and differences in the phases of molecular clock genes have been reported between nocturnal and diurnal species. Studies devoted to diurnal species, hence more relevant of human biology, are timely. In this context, zebrafish has emerged as a promising diurnal model for chronobiology.
Using zebrafish larvae as a model, we are analyzing the activity/regulation of the circadian clock in two different contexts: 1) the growth/specification of the zebrafish embryo 2) the neuronal circuit driving locomotor rhythms. These two different contexts will allow to compare the diversity of activities and presumed modes of action of the circadian system. We are developing a new transgenic reporter for the molecular clock associated with an image analysis pipeline that will be used in both contexts.
Project 1
– Alteration of the circadian rhythm either due to genetic mutations or to shift work causes cancer. Part of the detrimental effects of circadian perturbations on health lies in the fact that circadian clock actors control the cell cycle at several characterized steps. Interestingly, the cell cycle and the circadian clock have been shown to be synchronized in healthy tissue. This synchronization is altered in cancer cells. Synchronization of the cell cycle and the circadian clock was also described in zebrafish from day 4 to adult
– As the cell cycle in the early zebrafish embryo (day1) is less than 24 hours, we want to understand if a different form of synchrony exists early on (with for instance a regular rhythm of 3 cell cycle per circadian cycle, or specific cell cycle phases occurring only when specific clock genes are expressed). We will also analyze when the 1:1 synchrony is appearing during zebrafish development.
– In parallel, we will analyze how the circadian clock contributes to growth and specification of cell fates in the zebrafish embryo and larva using illumination conditions altering the clock activity as well as devoted genetic tools.
Project 2
Locomotor activity cycles quantitatively around the day. In the zebrafish larva, this rhythm is still present in absence of a functional eye but is impaired upon perturbation of clock activity in specific pineal cells. We have obtained evidence that the pineal gland is synaptically connected to the locomotor circuit.
– We will explore the role of the pineal gland in controlling locomotor activity quantitatively both through a neuronal circuit and the nocturnal secretion of melatonin.
– n parallel, through a collaboration with Claire Wyart (ICM, Paris), we are investigating the role of the circadian system and more specifically the pineal gland on qualitative aspects of locomotion (such as the type of movements and the characteristics of longer-term navigation).
– Finally using the transgenic reporter of the circadian clock, we will analyze whether the pineal gland synchronizes the molecular clock of neurons belonging to the locomotor circuit
– Altogether this project will contribute to our understanding of disease conditions where motor and circadian problems are associated such as RLS (Restless Leg Syndrome) and Parkinson Disease.
– Chaigne C, Sapède D, Cousin X, Sanchou L, Blader P, Cau E (2024) . Contribution of the eye and of opn4xa function to circadian photoentrainment in the diurnal zebrafish. PLoS Genet.
– Sapède D, Chaigne C, Blader P, Cau E (2020) Functional heterogeneity in the pineal projection neurons of zebrafish. Mol Cell Neurosci.
– Cau E. Ronsin B., Bessière L. and Blader P. (2019) A Notch-mediated, temporal asymmetry in BMP pathway activation promotes photoreceptor subtype diversification. PloS Biol.
– Sapède D, Cau E (2013). The pineal gland from development to function. Curr Top Dev Biol. (invited review)
– Quillien, A., Blanco-Sanchez, B., Halluin, C., Moore, J. C., Lawson, N., Blader, P. and Cau, E(2011) BMP signalling orchestrates photoreceptor specification in the zebrafish pineal gland in collaboration with Notch. Development.
– Cau. E and Blader.P (2009) Notch activity in the vertebrate nervous system: to switch or not to
– switch? Neural Dev. Review
– Cau. E. , Quillien, A *. and Blader, P (2008). Notch resolves mixed neural identities in the zebrafish epiphysis. Development.
Affiliation
