Molecular Mechanisms Underlying Terminal Nerve Development, GnRH-1 Neuronal Migration, and Olfactory Bulb Formation in Normal and Pathological Conditions - Summary The GnRH-1 neurons are fundamental for achieving sexual competence and fertility of vertebrates. During development, the GnRH-1 neurons migrate from the embryonic nasal area into the brain, where they will eventually take up positions in the hypothalamus to control the release of gonadotropins from the pituitary gland. Defects in GnRH-1 migration cause various forms of hypogonadotropic hypogonadism (HH) in humans, which is characterized by delayed pubertal onset, hypogonadism, and infertility. HH in humans manifests clinically as either Kallmann syndrome (KS) or normosmic idiopathic HH (nIHH). In KS, HH is associated with deficiencies in the sense of smell and olfactory bulb defects. Early migration of pioneer/ terminal nerve neurons from the olfactory placode is critical for triggering the formation of the olfactory bulbs, a necessary step for establishing a functional olfactory system. Our central hypothesis is that GnRH-1 neurons migrate to the hypothalamus on the Terminal Nerve (TN), and that the development of the TN is necessary to induce the formation of a functional olfactory system. We propose that genes that control TN development are distinct from those directly controlling the development of olfactory and vomeronasal sensory neurons. We further speculate that specific genetic mutations linked to KS and nIHH can negatively affect the pioneer/TN neurons in a cell-autonomous fashion, causing secondary GnRH-1 neuronal defective migration or mispositioning. Our preliminary data suggest that the neurons forming the Terminal Nerve have a distinct genetic from GnRH1, olfactory, and vomeronasal neurons. Moreover, we identified that several genes linked to KS, nIHH, and infertility are enriched in the TN neurons. In this study, we will genetically trace TN development and manipulate the TN to understand the developmental effects of genes linked to KS and niHH on the development of this nerve. By exploiting mouse genetics, cutting- edge imaging, single-cell sequencing, and human genomic data, we will discover fundamental cellular and molecular mechanisms underlying the normal and pathological development of the TN-GnRH-1 system in mammals. Successful completion of our study will define new transformative parameters for diagnostics and designing therapeutic approaches for KS and nIHH in humans.
