International Journal of Molecular Sciences

Review The Differential Roles for Neurodevelopmental and Neuroendocrine in Shaping GnRH Physiology and Deficiency

Roberto Oleari 1 , Valentina Massa 2,3 , Anna Cariboni 1,* and Antonella Lettieri 2,3,*

1 Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milano, Italy; [email protected] 2 Department of Health Sciences, University of Milan, 20142 Milano, Italy; [email protected] 3 CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milano, Italy * Correspondence: [email protected] (A.C.); [email protected] (A.L.)

Abstract: Gonadotropin releasing (GnRH) are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the , where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism  (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending  on their action in the GnRH neuronal system, CHH causative genes can be divided into neurode- Citation: Oleari, R.; Massa, V.; velopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple Cariboni, A.; Lettieri, A. The inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we Differential Roles for aim at providing a comprehensive and updated description of the genes thus far associated with Neurodevelopmental and CHH, by dissecting their biological relevance in the GnRH system and their functional relevance Neuroendocrine Genes in Shaping underlying CHH pathogenesis. GnRH Neuron Physiology and Deficiency. Int. J. Mol. Sci. 2021, 22, Keywords: GnRH neurons; congenital hypogonadotropic hypogonadism; Kallmann syndrome 9425. https://doi.org/10.3390/ ijms22179425

Academic Editor: Valentina Pallottini 1. Introduction Received: 2 August 2021 Fertility and reproduction of sexually reproducing species strictly depend on a Accepted: 28 August 2021 functional hypothalamic–pituitary–gonads (HPG) axis, which ensures gonadal devel- Published: 30 August 2021 opment, puberty onset and reproductive capacity. The HPG axis is a neuroendocrine circuit centrally regulated by hypothalamic Publisher’s Note: MDPI stays neutral gonadotropin-releasing hormone (GnRH) neurons, which, in humans, release the GnRH with regard to jurisdictional claims in decapeptide in a pulsatile fashion within the pituitary blood portal system to stimulate go- published maps and institutional affil- nadotrope cells to secrete gonadotropins (i.e., LH and FSH). Once released, gonadotropins iations. reach, through circulation, the gonads, where they induce sex steroid production [1]. Because the neurohormone GnRH is the primary driver of the HPG axis, proper development and function of its producing neurons is required. In this context, several factors finely regulate GnRH neuron physiology by acting at different levels, including Copyright: © 2021 by the authors. GnRH neuron development and differentiation, GnRH synthesis, secretion and action. Licensee MDPI, Basel, Switzerland. Accordingly, defects in either GnRH neuron development or function can lead to a patho- This article is an open access article logical condition known as isolated GnRH deficiency or Congenital Hypogonadotropic distributed under the terms and Hypogonadism (CHH), characterized by incomplete or absent puberty