Core Circadian TTFL Molecular Regulatory Diagram in Zebrafish.

This figure illustrates the core transcription-translation feedback loop (TTFL) and auxiliary regulatory network of the zebrafish circadian clock. Clock (clock1a/1b) and Bmal (bmal1/2) form heterodimers, which bind E-box (CACGTG) elements to activate the transcription of the Per (per1/2/3) and Cry (cry1a/1b/3a/3b) genes. Cytoplasmic Per/Cry complexes, which are phosphorylated by CK1δ/ε kinases, translocate into the nucleus to inhibit Clock/Bmal activity, resulting in a 24-hour oscillation. Per/Cry is rhythmically degraded via the ubiquitin-proteasome system to relieve inhibition. Auxiliary loops involve Rev-Erbα/RORα (e.g., roraa) competitively regulating Bmal via RORE, whereas Tef (PAR bZIP family) mediates light-core clock coupling through D-box elements.

Schematic Diagram of Zebrafish Retinal Photoreceptors, Deep Brain Photoreceptors, and Peripheral Photoreceptors and their Roles in Circadian Photoentrainment.

This figure depicts three core light-sensing systems that mediate zebrafish circadian photoentrainment and light-driven behaviors. The zebrafish retina directly integrates light signals with its biological rhythms via its intrinsic molecular clock, enabling the regulation of behavioral rhythms. Distributed deep-brain photoreceptors form a non-visual light perception system essential for phase entrainment. Zebrafish possess a decentralized circadian system, with peripheral tissues/organs sustaining autonomous oscillations and responding directly to light via photopigments and ROS signaling.

The distribution of photoproteins in various tissues of zebrafish and mice.

This figure shows the distribution of all opsin classes in zebrafish and mouse, two representative vertebrate species. Presence is marked as Y and absence as N. Opsins are classified into six major groups: (1) visual opsins (green), (2) cone-like non-visual opsins (blue), (3) opn3/tmt opsins (purple), (4) rgr/rrh/opn5 opsins (yellow), (5) opn4 opsins (black), and (6) the new opsins (red). (Figure 3 adapted from Figure 3 from [70])

Circadian Clock’s Regulatory Network for Zebrafish Multi-System Physiology.

This figure centers on zebrafish to illustrate the regulation of multi-system physiological functions by the circadian clock. The functional modules involved include: (1) the nervous system, encompassing sleep-wake cycles, learning and memory, and synaptic plasticity; (2) the cardiovascular system, including heart rate, cardiac output, and vascular development and regeneration; (3) the metabolic system, covering lipid and glucose metabolism as well as detoxification; (4) the reproductive system, involving spermatogonial differentiation and fertilization, ovarian reserve and tumorigenesis, and maternal clock inheritance; (5) the intestinal system, comprising epithelial cell renewal and gut microbiota homeostasis. The associations between these functional modules and zebrafish reflect the coordinated control of the circadian clock over multiple physiological systems.

The immune system is regulated by the circadian rhythm.

This figure illustrates the diurnal variation of neutrophils in the model of bacterial infection and tail fin injury in zebrafish larvae. clock1a gene regulates neutrophil migration by coordinating the rhythmic expression of nfe212a and duox genes to control the reactive oxygen species (ROS) level. Light-regulated Per2 increases reactive oxygen species (ROS) production and bacterial killing in zebrafish neutrophils by controlling Hmgb1 expression.