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Abstract  Molecular decision‐makers of photoreceptor (PRC) membrane organization and gene regulation are critical to understanding sight and retinal degenerations that lead to blindness. Using  Mfrp rd6   mice, which develop PRC degeneration, we uncovered that membrane‐type frizzled‐related protein (MFRP) participates in docosahexaenoic acid (DHA, 22:6) enrichment in a manner similar to adiponectin receptor 1 (AdipoR1). Untargeted imaging mass spectrometry demonstrates cell‐specific reduction of phospholipids containing 22:6 and very long‐chain polyunsaturated fatty acids (VLC‐PUFAs) in  Adipor1 −/−   and  Mfrp rd6   retinas. Gene expression of pro‐inflammatory signaling pathways is increased and gene‐encoding proteins for PRC function decrease in both mutants. Thus, we propose that both proteins are necessary for retinal lipidome membrane organization, visual function, and to the understanding of the early pathology of retinal degenerative diseases.

Membrane‐type frizzled‐related protein regulates lipidome and transcription for photoreceptor function