ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 7.11 | DOI: 10.1530/ey.15.7.11

Service of Endocrinology, Diabetology & Metabolism, Lausanne University Hospital, Lausanne, Switzerland


To read the full abstract: EMBO Mol Med. 2017 Oct;9(10):1379-1397

[Comments on 7.10 and 7.11] During embryonic development, GnRH neurons originate in the olfactory placode and migrate through the nasal mesenchyme using the olfactory/vomeronasal axons as a scaffold to reach their final destination in the basal forebrain1,2. This migratory process has been well-described in rodents, and is tightly controlled by a complex network of genes encoding molecular cues that drive GnRH neuron motility, cell adhesion and directionality2. Defects disrupting the genesis, migration of GnRH neurons and/or synthesis and secretion of GnRH in humans can lead to congenital hypogonadotropic hypogonadism (CHH). Alteration of the prenatal development and/or migration of GnRH neurons is generally associated with Kallmann syndrome (KS), and disruption of the synthesis, release or signaling of GnRH is commonly associated with normosmic CHH (nCHH). The two studies summarized here illustrate the role of new factors involved in GnRH neurons development and migration.

First, Bouilly et al. tested a hypothesis based on the observation that causal mutations in CHH have illustrated the crucial role of fibronectin type 3 (FN3)-domain containing proteins in GnRH neuron development. For this reason, using whole exome sequencing in CHH patients, the authors filtered their results to include only those genes encoding proteins containing FN3-domains. This strategy identified rare sequence variants in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). Probands had severe GnRH deficiency with absent puberty, and all males had a history of micropenis with/without cryptorchidism. In vitro analysis revealed that all identified NTN1 and DCC variants do not impair transcript or protein expression but modify biological activity and causes signaling defects. NTN1 mutations affected GnRH neuron migration using immortalized GnRH neurons cell motility assays. Netrin-1 and DCC are expressed in the developing human vomeronasal organ (VNO), the surrounding tissue extending from the VNO towards the forebrain, and in GnRH neurons. Moreover, Netrin-1 was also expressed in other cell types belonging to the migratory cell population. In summary, this study further illustrates the role of loss-of-function mutations in FN3-domain encoding proteins in CHH. This underlines the role of these proteins in cell migration and axonal guidance in GnRH neurons during embryonic development.

Secondly, Xu et al. hypothesized that defects in the FGF21/KLB/FGFR1 signaling pathway may underlie GnRH deficiency in both humans and rodents. Fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in GnRH neuron fate specification during embryonic life, but also in GnRH network homeostasis and FGFR1 mutations are present in approximately 10% of CHH cases and are often associated with incomplete penetrance and variable expressivity. The authors noted that a CHH FGFR1 mutation decreased signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with b-Klotho (KLB), the obligate co-receptor for FGF21. Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function Klb mutations. The clinical spectrum ranged from severe GnRH deficiency with micropenis and cryptorchidism to milder forms such as CHH with reversal or fertile eunuch syndrome. All Klb mutants were confirmed to be loss of function in vitro as well as in vivo using a rescue assay in C. elegans. Klb deficient mice showed a normal distribution of hypothalamic GnRH neurons and axonal projections to the median eminence, indicating normal embryonic GnRH neurons development. However, they exhibited delayed puberty and subfertility due to a hypothalamic defect. Intraperitoneal injection of Kisspeptin injections also induced LH secretion in both wild-type and Klb knock-out females, suggesting that GnRH neurons were present and could respond to stimulation. These results implicate Klb in hypothalamic GnRH secretion. Klb mutations impair FGF21 signaling in patients with congenital GnRH deficiency with a high frequency of associated metabolic defects. This supports the key role of the hepatokine FGF21, as a key link between metabolism and reproduction.

1. Schwanzel-Fukuda, M. and Pfaff, D.W. Origin of luteinizing hormone-releasing hormone neurons. Nature 1999; 338: 161–164.

2. Wierman, M.E., Kiseljak-Vassiliades, K. and Tobet, S. Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front. Neuroendocrinol. 2011; 32: 43–52.

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