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Endocrine Abstracts (2022) 81 OC12.3 | DOI: 10.1530/endoabs.81.OC12.3

1Istituto Auxologico Italinao, Dept of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Milan, Italy; 2University of Milan, Dept of Medical Biotechnology and Translational Medicine, University of Milan, Milan Italy; 3, Univ. Lille, Inserm, CHU Lille, U1172 -LilNCog(JPARC) –Lille Neurosciences & Cognition, F-59000, Lille, France, Lille, France; 4Lausanne University Hospital, Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland


The precise development of the Gonadotropin Releasing Hormone (GnRH) neurons is essential for the proper function of the hypothalamic-pituitary-gonadal axis, as GnRH is the master regulator of reproductive functions in vertebrates. Mutations in genes involved in the development of GnRH neurons are associated with Congenital Hypogonadotropic Hypogonadism (CHH), a heterogeneous genetic disorder characterized by hypogonadism, lack of puberty onset, and infertility, which is named Kallmann Syndrome (KS) when the disease associates with anosmia. In this study, we identified in two European cohorts of CHH/KS patients rare missense variants in the NOTCH1 ligand gene JAG1. It is already reported in the literature the key role of the Notch signaling in the development of the olfactory system in both mouse and drosophila; therefore, considering the intimate connection between the olfactory and GnRH systems we studied its possible role in the development of the GnRH system. We first performed multiplex fluorescent in situ hybridization combined with immunofluorescence to assess the expression pattern of JAG1 and its receptors NOTCH1, NOTCH2, NOTCH3 and NOTCH4 in human fetal sections of the nasal compartment during the first trimester of gestation. We showed that those molecules were expressed along the GnRH migratory pathway as well as by GnRH neurons, suggesting a paracrine and/or autocrine mechanism. Taking advantage of the zebrafish model, we observed that jag1a, jag1b, notch1a, and GnRH3 (homologous of the mammalian GnRH1) were expressed in the olfactory placodes of zebrafish embryos. Moreover, we report that pharmacological and genetic inhibition of jag1b altered the development of the GnRH3 neurons and the olfactory scaffold used for their migratory process. Functional in vitro validation of the JAG1 variants identified in CHH patients revealed that some were retained into the cytoplasm and did not reach the cell membrane. We also showed that some variants did not properly activate the Notch Responsive Element, suggesting that they are loss-of-function mutations. Combining morphological analysis in vivo, together with genetic manipulation in zebrafish and human genetic analysis, we provide compelling evidence that Notch1/Jag1 signaling plays a role in the development of GnRH neurons and propose that Notch1/Jag1 signaling insufficiency may contribute to the pathogenesis of CHH in humans.

Key words: CHH, KS, GnRH, Notch signaling, Reproduction

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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