Dimerization of melanocortin 4 receptor controls puberty onset and body size polymorphism

• Published in: Frontiers in endocrinology (Lausanne) Vol. 14; p. 1267590
• Main Authors: Liu, Ruiqi, Friedrich, Mike, Hemmen, Katherina, Jansen, Kerstin, Adolfi, Mateus C, Schartl, Manfred, Heinze, Katrin G
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2023
• Subjects: Animals; Body Size; Dimerization; fluorescence lifetime imaging microscopy; Förster Resonance Energy Transfer; Male; Mc4r; Polymorphism, Genetic; puberty; Receptor, Melanocortin, Type 4 - genetics; Receptor, Melanocortin, Type 4 - metabolism; Sexual Maturation; Xiphophorus; Mc4r; Xiphophorus; Förster Resonance Energy Transfer; puberty; fluorescence lifetime imaging microscopy
• DOI: 10.3389/fendo.2023.1267590
• ISSN: 1664-2392

fish exhibit a clear phenotypic polymorphism in puberty onset and reproductive strategies of males. In and , puberty onset is genetically determined and linked to a melanocortin 4 receptor (Mc4r) polymorphism of wild-type and mutant alleles on the sex chromosomes. We hypothesized that Mc4r mutant alleles act on wild-type alleles by a dominant negative effect through receptor dimerization, leading to differential intracellular signaling and effector gene activation. Depending on signaling strength, the onset of puberty either occurs early or is delayed. Here, we show by Förster Resonance Energy Transfer (FRET) that wild-type Mc4r monomers can form homodimers, but also heterodimers with mutant receptors resulting in compromised signaling which explains the reduced Mc4r signaling in large males. Thus, hetero- homo- dimerization seems to be the key molecular mechanism for the polymorphism in puberty onset and body size in male fish.