Zebrafish (Danio rerio) has emerged as one of the most widely used animal models in basic and translational research. Several advantages account for this popularity: a genome that shares a high degree of similarity with that of humans, the ease of genetic and chemical manipulation, external fertilization combined with high fecundity, transparent and rapidly developing embryos, as well as a moderate maintenance cost. Body translucency, a property rarely accessible in other vertebrates, makes this animal an ideal subject for optical modulation and observation. Added to this are the convenience of micro-injection and the high permeability of embryos, which allow the efficient introduction of molecules of all sizes into the living animal, while the large number of offspring from a single mating pair provides numerous replicates and improves the statistical analysis of results.
This review traces the development of opto-chemical tools, which exploit light-activatable molecules to control biological activities with high spatiotemporal resolution. The authors distinguish these approaches from optogenetics, which is based on the engineering of light-sensitive proteins and is addressed elsewhere. Two major opto-chemical strategies are described: photo-induced conformational change, in which chromophores switch between isomeric forms to reversibly activate or inactivate the associated proteins (hence the term photoswitches), and photo-induced release, which relies on the chemical "caging" of small molecules, oligonucleotides, peptides, or proteins. The review illustrates these principles with applications reported in zebrafish, notably in the study of tissue injury and regeneration, a field in which the animal exhibits a capacity to regenerate numerous tissues and organs. Examples discussed include targeted cell ablation through optical expression of a cytotoxic channel, the stimulation of neuronal regeneration via a photoactivatable adenylate cyclase, and photoswitchable ligands targeting the β1-adrenergic receptor to disrupt cardiac rhythm.
The authors highlight the persistent challenges of these still-emerging technologies. Photosensitivity remains a central issue: molecules may become activated in the absence of the intended light stimulus ("leaky" activity), which necessitates rigorous controls—without inducing light on the one hand, and under illumination alone on the other—since UV and blue light, as well as heat, can cause cellular damage. The diffusion of released molecules may further limit spatial resolution, a problem that strategies such as covalent anchoring of ligands or multiphoton excitation can help to mitigate. Finally, the authors advocate for close collaboration between chemists, biologists, and biophysicists, and for the commercialization or facilitated sharing of these reagents. They conclude that opto-chemistry, a rapidly growing field, holds considerable potential, including for translational purposes, and that the optimization of existing tools will further broaden their range of applications.