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LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling
Alessandra Mancini, … , Leonardo Guasti, Leo Dunkel
Alessandra Mancini, … , Leonardo Guasti, Leo Dunkel
Published June 4, 2020
Citation Information: JCI Insight. 2020;5(11):e133434. https://doi.org/10.1172/jci.insight.133434.
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Research Article Endocrinology Reproductive biology

LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling

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Abstract

The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/β-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/β-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/β-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.

Authors

Alessandra Mancini, Sasha R. Howard, Federica Marelli, Claudia P. Cabrera, Michael R. Barnes, Michael J.E. Sternberg, Morgane Leprovots, Irene Hadjidemetriou, Elena Monti, Alessia David, Karoliina Wehkalampi, Roberto Oleari, Antonella Lettieri, Valeria Vezzoli, Gilbert Vassart, Anna Cariboni, Marco Bonomi, Marie Isabelle Garcia, Leonardo Guasti, Leo Dunkel

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Figure 4

Lgr4–/– female mice fail to enter puberty and show reduced number of GnRH neurons during fetal and adult life.

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Lgr4–/– female mice fail to enter puberty and show reduced number of Gn...
(A) Vaginal opening for pubertal onset shows that Lgr4+/– mice have a significant (*P = 0.01) delayed onset of puberty compared with Lgr4+/+. Lgr4–/– female mice fail to enter puberty completely. Lgr4+/+ n = 10, Lgr4+/– n = 23, Lgr4–/– n = 7. (B) Lgr4+/– mice are not smaller than Lgr4+/+, as shown by the percentage relative to Lgr4+/+. Lgr4+/+, n = 10; Lgr4+/–, n = 15. (C) Litter size is not affected when pairing Lgr4+/+ with Lgr4+/–. Crosses between Lgr4+/+ × Lgr4+/+ and Lgr4+/+ × Lgr4+/– harbor a normal number in litter size, proving that fertility is not affected in Lgr4+/– males and females. Lgr4+/+, n = 10; Lgr4+/–, n = 23. (D–F) Show gross anatomy of Lgr4+/+, Lgr4+/–, and Lgr4–/– reproductive tracts, respectively. (G–I) Show gross anatomy of Lgr4+/+, Lgr4+/–, and Lgr4–/– ovaries, respectively. (J) Lgr4–/– females show reproductive tracts significantly reduced in weight compared with Lgr4+/+ females (*P = 0.0366); n = 3. Scale bars: 2.5 mm (D–F), 1 mm (G–I). (K–M) GnRH neurons number in E12.5, E16.5, and adults, respectively. In K, Lgr4+/+ = 3, Lgr4+/– = 3, Lgr4–/– = 2; in L, Lgr4+/+ = 2, Lgr4+/– = 4, Lgr4–/– = 3; in M, Lgr4+/+ = 5, Lgr4+/– = 3, Lgr4–/– = 3. In all groups, Lgr4–/– mice show a reduced number of GnRH neurons compared with Lgr4+/+. (Adults, *P = 0.0265). Lgr4+/– mice show a similar trend although not statistically significant. Unpaired 2-tailed t test was used for statistical analysis for (A–C) and (J). Kruskal-Wallis test was used for M.

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