PUBLICATION
Defective Jagged1 signaling impacts GnRH development and contributes to congenital hypogonadotropic hypogonadism
- Authors
- Cotellessa, L., Marelli, F., Duminuco, P., Adamo, M., Papadakis, G.E., Bartoloni, L., Sato, N., Lang-Muritano, M., Troendle, A., Dhillo, W.S., Morelli, A., Guarnieri, G., Pitteloud, N., Persani, L., Bonomi, M., Giacobini, P., Vezzoli, V.
- ID
- ZDB-PUB-230203-18
- Date
- 2023
- Source
- JCI insight 8(5): (Journal)
- Registered Authors
- Keywords
- Development, Fertility, Genetic diseases, Genetics, Neurodevelopment
- MeSH Terms
-
- Animals
- Female
- Gonadotropin-Releasing Hormone*/genetics
- Humans
- Hypogonadism*/genetics
- Jagged-1 Protein/genetics
- Pregnancy
- Signal Transduction
- Zebrafish
- PubMed
- 36729644 Full text @ JCI Insight
Citation
Cotellessa, L., Marelli, F., Duminuco, P., Adamo, M., Papadakis, G.E., Bartoloni, L., Sato, N., Lang-Muritano, M., Troendle, A., Dhillo, W.S., Morelli, A., Guarnieri, G., Pitteloud, N., Persani, L., Bonomi, M., Giacobini, P., Vezzoli, V. (2023) Defective Jagged1 signaling impacts GnRH development and contributes to congenital hypogonadotropic hypogonadism. JCI insight. 8(5):.
Abstract
In vertebrate species, fertility is controlled by gonadotropin-releasing hormone (GnRH) neurons. GnRH cells arise outside the central nervous system, in the developing olfactory pit, and migrate along olfactory/vomeronasal/terminal nerve axons into the forebrain during embryonic development. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare genetic disorders characterized by infertility and they are associated with defects in GnRH neuron migration and/or altered GnRH secretion and signaling.Here, we documented the expression of Jagged 1/Notch signaling pathway in GnRH neurons and along the GnRH neuron migratory route both in zebrafish embryos and in human fetuses. Genetic knock-down of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulbs.Next-generation sequencing was performed in 467 CHH unrelated probands leading to the identification of heterozygous rare variants in JAG1. Functional in vitro validation of JAG1 mutants revealed that 7 out of the 9 studied variants exhibit reduced protein levels and altered subcellular localization.Altogether our data provide compelling evidence that Jag1/Notch signaling plays a prominent role in the development of GnRH neurons and we propose that JAG1 insufficiency may contribute to the pathogenesis of CHH in humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping