GPR37 Signaling Modulates Migration of Olfactory Ensheathing Cells and Gonadotropin Releasing Hormone Cells in Mice.

Hassan Saadi,Yufei Shan,Susan Wray,Daniela Marazziti

doi:10.3389/fncel.2019.00200

Abstract

Gonadotropin releasing hormone (GnRH) neurons, part of the hypothalamic-pituitary-gonadal axis, regulate reproduction. Prenatally, GnRH neurons migrate into the brain from the nasal placode along terminal nerve fibers, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37 (GPR37 or PAEL-r). GPR37 has been linked to (1) juvenile Parkinson’s disease in humans, (2) oligodendrocyte differentiation, and (3) Wnt/β-catenin signaling during neurogenesis. In this study, the role of GPR37 was investigated in the developing GnRH/olfactory system. PCR and immunocytochemistry confirmed expression of GPR37 in migrating GnRH neurons as well as in OECs. Inhibition of GPR37 signaling in nasal explants attenuated GnRH neuronal migration and OEC movement. Examination of GPR37 deficient mice revealed a decrease in the olfactory bulb nerve layer and attenuated/delayed maturation and migration of GnRH neurons into the brain. These data demonstrate a developmental role for GPR37 signaling in neural migration.Significance StatementReproduction is controlled by gonadotrophin releasing hormone (GnRH) neurons located in the central nervous system. Embryonically, GnRH neurons originate in the nasal/olfactory placode and migrate into the brain on axonal tracks from cells in the vomeronasal organ, intermixed with olfactory sensory axons and olfactory ensheathing cells (OECs). An expression analysis from embryonic GnRH neurons identified the G protein-coupled receptor 37. Here we show that inhibition of GPR37 signaling in nasal explants and mutant mice attenuated GnRH neuronal migration. Signaling via GPR37 also perturbed OEC movement, resulting in a decrease in the olfactory bulb nerve layer in vivo. Together, these results identify a new role for GPR37 signaling during development – modulating cell migration.

Highlights

gonadotrophin releasing hormone (GnRH) neurons form a functional circuit as part of the hypothalamic-pituitary-gonadal axis and control reproduction
Since GnRH cells migrate in association with olfactory ensheathing cells (OECs) along olfactory axons, G protein-coupled receptor 37 (GPR37) expression in OECs and sensory axons was examined at E12.5, when both axons and OECs are robust in the migratory tracts (Figure 3)
We characterized the expression of GPR37 in the developing GnRH/olfactory system and identified a novel role for PSAP-GPR37 signaling on GnRH and OEC migration and neurogenesis

Summary

Introduction

GnRH neurons form a functional circuit as part of the hypothalamic-pituitary-gonadal axis and control reproduction. Genetic studies of human patients with hypogonadotropic hypogonadism and anosmia, Kallman’s Syndrome, have identified a variety of molecules that influence GnRH neuronal migration and/or olfactory development (Wray, 2010; Topaloglu, 2017; Bouilly et al, 2018). To uncover novel regulators of GnRH neuronal development, a microarray screen was performed (Kramer and Wray, 2000; Dairaghi et al, 2018), and identified G protein-coupled receptor 37 (GPR37). Data from the Allen Developing Mouse Brain Atlas (2008) (Sunkin et al, 2013) and the Gene Expression Nervous System Atlas (GENSAT) project (Gong et al, 2003) confirmed developmental expression of GPR37 transcript and protein, respectively, in nasal regions that corresponded to the migratory route of GnRH neurons in mice

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