Imperial College London
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DrAlessiaDavid

Faculty of Natural Sciences, Department of Life Sciences

Lecturer in Bioinformatics and Data Intensive Biology
 
 
 
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Contact

 

+44 (0)20 7594 5333alessia.david09

 
 
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Location

 

Department of BioinformaticsSir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Mancini:2020:10.1172/jci.insight.133434,
author = {Mancini, A and Howard, SR and Marelli, F and Cabrera, CP and Barnes, MR and Sternberg, MJ and Leprovots, M and Hadjidemetriou, I and Monti, E and David, A and Wehkalampi, K and Oleari, R and Lettieri, A and Vezzoli, V and Vassart, G and Cariboni, A and Bonomi, M and Garcia, MI and Guasti, L and Dunkel, L},
doi = {10.1172/jci.insight.133434},
journal = {JCI insight},
pages = {1--17},
title = {LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling},
url = {http://dx.doi.org/10.1172/jci.insight.133434},
volume = {5},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Mancini,A
AU  - Howard,SR
AU  - Marelli,F
AU  - Cabrera,CP
AU  - Barnes,MR
AU  - Sternberg,MJ
AU  - Leprovots,M
AU  - Hadjidemetriou,I
AU  - Monti,E
AU  - David,A
AU  - Wehkalampi,K
AU  - Oleari,R
AU  - Lettieri,A
AU  - Vezzoli,V
AU  - Vassart,G
AU  - Cariboni,A
AU  - Bonomi,M
AU  - Garcia,MI
AU  - Guasti,L
AU  - Dunkel,L
DO  - 10.1172/jci.insight.133434
EP  - 17
PY  - 2020///
SN  - 2379-3708
SP  - 1
TI  - LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling
T2  - JCI insight
UR  - http://dx.doi.org/10.1172/jci.insight.133434
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32493844
UR  - https://insight.jci.org/articles/view/133434
UR  - http://hdl.handle.net/10044/1/80025
VL  - 5
ER  -
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