Molecular delineation of a retina-dependent photoneuroendocrine pathway in zebrafish

Many vertebrates, including fish, amphibians, and reptiles, dynamically adjust their body color to the perceived brightness of the ambient background. This response takes tens of minutes and involves the aggregation or dispersion of pigment granules within the melanophores of the skin, resulting in the pale or dark appearance of the animal, respectively.¹ In teleosts, ambient light detection depends on the retina, which transmits the signal to the hypothalamus, leading to the secretion of peptide hormones via the pituitary gland into the bloodstream. Melanin-concentrating hormone (MCH) is released upon light stimulation, resulting in the blanching of the skin. Alpha-melanocyte-stimulating hormone (α-MSH, encoded by the pomca gene and produced in the hypothalamus and pituitary) has the opposite effect: light inhibits its secretion, leading to melanin dispersion in the skin.^1,2,3,4,5 Because "dark appearance" is an easy-to-score phenotype in larval zebrafish, defective visual background adaptation (VBA) has been used in genetic screens as a proxy for retinal defects,^6,7 but the responsible neuroendocrine circuit remained elusive. Here, we identified the molecular and cellular components underlying this response. We found that intrinsically photosensitive retinal ganglion cells (ipRGCs), expressing the homeobox transcription factor Onecut1, project to the neuropil region of the preoptic area, where their axons overlap with the dendrites of pmchl-expressing hypothalamic neurons. Signals from these ipRGCs increase the transcription of pmchl, one of two genes encoding MCH isoforms, and repress pomca. Ablation of either onecut1-positive ipRGCs or pmchl-expressing hypothalamic neurons prevents the fish larva from adapting to a bright background.