Lahne, M.; Lungu, R.; Snorton, M.; Yoshimatsu, T.; MacDonald, R. B.

Neurons of the same type can be differentially tuned to perform distinct functional roles, yet how such specialisation arises during development remains poorly understood. Here, we show that in the zebrafish retina, heterogeneity within a single glial population generates local gradients of retinoic acid (RA) signalling that fine-tune neural function within a single neuronal type. The acute zone (AZ), a ventro-temporal region of the retina, is specialised for prey capture in the upper frontal visual field. In this region, UV cones exhibit enhanced light sensitivity through elongation of their outer segments (OS), the cellular compartment responsible for phototransduction. We found that cyp26 genes, which encode RA-degrading enzymes, are expressed in Muller glia in a region-specific manner, and that this expression pattern closely matches the spatial variation in cone OS length. Inhibition of Cyp26 activity prevented OS elongation in the AZ. This effect is mediated by RA signalling, as direct activation of RA receptors using RAR agonists similarly reduced OS length in this region. Notably, inhibition of Cyp26 predominantly activated RA signalling in Muller glia rather than in cones, indicating that RA signalling regulates cone OS length in a cell-non-autonomous manner via Muller glia. Consistent with this model, blocking Muller glia genesis abolished cone specialisation across all regions of the developing retina. Together, these findings identify Muller glia as key regulators of cone functional specialisation through the spatial control of RA signalling.