Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
John Falardeau, … , Pei Tsai, Nelly Pitteloud
John Falardeau, … , Pei Tsai, Nelly Pitteloud
Published July 1, 2008
Citation Information: J Clin Invest. 2008;118(8):2822-2831. https://doi.org/10.1172/JCI34538.
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Research Article Reproductive biology

Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adult-onset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling.

Authors

John Falardeau, Wilson C.J. Chung, Andrew Beenken, Taneli Raivio, Lacey Plummer, Yisrael Sidis, Elka E. Jacobson-Dickman, Anna V. Eliseenkova, Jinghong Ma, Andrew Dwyer, Richard Quinton, Sandra Na, Janet E. Hall, Celine Huot, Natalie Alois, Simon H.S. Pearce, Lindsay W. Cole, Virginia Hughes, Moosa Mohammadi, Pei Tsai, Nelly Pitteloud

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Figure 6

Study of GnRH neurons in Fgf8 hypomorphic mice.

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Study of GnRH neurons in Fgf8 hypomorphic mice. (A–F) GnRH ICC illus...
(A–F) GnRH ICC illustrating the complete absence of GnRH neuron fibers and cell bodies in P0 homozygous Fgf8 hypomorphic mice (C and F) in the preoptic area and median eminence (ME) compared with WT controls (A and D) and heterozygous mice (B and E). Arrows denote GnRH neuron cell bodies; arrowheads denote GnRH fibers. Asterisks and dotted lines delineate the medial aspects of the brain. OVLT, organum vasculosum of the lamina terminalis. Scale bars: 100 μm. (G and H) The level of immunoreactive GnRH markedly decreased in Fgf8 heterozygotes at all postnatal ages measured. (H) Distribution of GnRH neurons in the preoptic-hypothalamic area of P29 WT controls and Fgf8 heterozygotes. Numbers in the x axis indicate increments of 40-μm sections. Negative and positive numbers indicate sections rostral and caudal to the organum vasculosum of the lamina terminalis (denoted 0), respectively. The distribution of GnRH neurons was largely normal in the transgenic mice, except that there were fewer GnRH neurons. Fgf8 heterozygotes had markedly fewer GnRH neurons in the preoptic-hypothalamic area compared with age-matched controls. ND, not detected. Data are mean ± SEM. *P < 0.05.