Developmental Expression of Orphan G Protein-Coupled Receptor 50 in the Mouse Brain

Abstract

Mental disorders have a complex etiology resulting from interactions between multiple genetic risk factors and stressful life events. Orphan G protein-coupled receptor 50 (GPR50) has been identified as a genetic risk factor for bipolar disorder and major depression in women, and there is additional genetic and functional evidence linking GPR50 to neurite outgrowth, lipid metabolism, and adaptive thermogenesis and torpor. However, in the absence of a ligand, a specific function has not been identified. Adult GPR50 expression has previously been reported in brain regions controlling the HPA axis, but its developmental expression is unknown. In this study, we performed extensive expression analysis of GPR50 and three protein interactors using rt-PCR and immunohistochemistry in the developing and adult mouse brain. Gpr50 is expressed at embryonic day 13 (E13), peaks at E18, and is predominantly expressed by neurons. Additionally we identified novel regions of Gpr50 expression, including brain stem nuclei involved in neurotransmitter signaling: the locus coeruleus, substantia nigra, and raphe nuclei, as well as nuclei involved in metabolic homeostasis. Gpr50 colocalizes with yeast-two-hybrid interactors Nogo-A, Abca2, and Cdh8 in the hypothalamus, amygdala, cortex, and selected brain stem nuclei at E18 and in the adult. With this study, we identify a link between GPR50 and neurotransmitter signaling and strengthen a likely role in stress response and energy homeostasis. KEYWORDS: GPR50, Nogo-A, Cadherin 8, ABCA2, rt-PCR, immunohistochemistry P sychiatric disorders are a major health problem in the world today. One in four people are affected by mental disorders during their lives, according to the World Health Organization. 1 Psychiatric illness results from the interaction between genetic and environmental risk factors. There is a strong genetic component, as is clear from family, twin, and adoption studies. 2 Recently, G protein-coupled receptor 50 (GPR50) was identified as a risk gene for bipolar disorder and major depression in Scottish women. 3,4 GPR50, previously known as the melatoninrelated receptor, is the mammalian ortholog of the melatonin 1c receptor (Mel1c). 5 Despite a 45% sequence identity to melatonin receptors MT1 and MT2, it does not bind melatonin or any other ligand and therefore remains an orphan receptor without a clear function. 6,7 We have recently reported the results of a yeast two-hybrid study (Y2H), identifying interactors with the relatively large GPR50 C-terminal domain. 8 Interactors can be grouped into two functional classes by gene ontology: neural development and sterol metabolism, indicating a likely role in these mechanisms. In addition, we showed that GPR50 has a dramatic effect on the neurite outgrowth, supporting a likely role in neural development. 8 Although the list of interactors includes several interesting protein partners, we know little about where and when these proteins could interact and what function the interactions would have.Functional evidence for a lin...

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