PUBLICATION
LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling
- Authors
- Mancini, A., Howard, S.R., Marelli, F., Cabrera, C.P., Barnes, M.R., Sternberg, M.J., Leprovots, M., Hadjidemetriou, I., Monti, E., David, A., Wehkalampi, K., Oleari, R., Lettieri, A., Vezzoli, V., Vassart, G., Cariboni, A., Bonomi, M., Garcia, M.I., Guasti, L., Dunkel, L.
- ID
- ZDB-PUB-200606-4
- Date
- 2020
- Source
- JCI insight 5(11): (Journal)
- Registered Authors
- Keywords
- Endocrinology, G-protein coupled receptors, Molecular genetics, Neuroendocrine regulation, Reproductive Biology
- MeSH Terms
-
- Animals
- Female
- Follow-Up Studies
- Gonadotropin-Releasing Hormone/genetics
- Gonadotropin-Releasing Hormone/metabolism
- Humans
- Male
- Mice
- Neurons*/metabolism
- Neurons*/pathology
- Puberty, Delayed*/genetics
- Puberty, Delayed*/metabolism
- Puberty, Delayed*/pathology
- Receptors, G-Protein-Coupled/deficiency*
- Receptors, G-Protein-Coupled/metabolism
- Wnt Signaling Pathway*
- beta Catenin/genetics
- beta Catenin/metabolism
- PubMed
- 32493844 Full text @ JCI Insight
Citation
Mancini, A., Howard, S.R., Marelli, F., Cabrera, C.P., Barnes, M.R., Sternberg, M.J., Leprovots, M., Hadjidemetriou, I., Monti, E., David, A., Wehkalampi, K., Oleari, R., Lettieri, A., Vezzoli, V., Vassart, G., Cariboni, A., Bonomi, M., Garcia, M.I., Guasti, L., Dunkel, L. (2020) LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling. JCI insight. 5(11):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping