ESPEYB20 5. Puberty Basic Research (6 abstracts)
5.12. Defective jagged-1 signaling affects GnRH development and contributes to congenital hypogonadotropic hypogonadism
Cotellessa L , Marelli F , Duminuco P , Adamo M , Papadakis GE , Bartoloni L , Sato N , Lang-Muritano M , Troendle A , Dhillo WS , Morelli A , Guarnieri G , Pitteloud N , Persani L , Bonomi M , Giacobini P & Vezzoli V
JCI Insight. 2023;8(5):e161998.PMID: 36729644. https://insight.jci.org/articles/view/161998
Brief summary: Using a combination of expression studies in human embryos as well as functional studies in zebrafish and genetic sequencing of patient with congenital hypogonadotropic hypogonadism, this study identified a novel role for Jag1/Notch signaling in the development of GnRH neurons.
GnRH neurons have a unique characteristic as they start life in the olfactory placode and then migrate into the hypothalamus during embryonic development, thanks to a complex network of factors involved in cell adhesion, cell migration and neurite outgrowth (1). It is now well established that defects in GnRH neuron migration cause congenital hypogonadotropic hypogonadism (2).
Notch1 is a signaling molecule which interacts with Notch ligands, such as Jagged-1 on adjacent cells (3). Notch1 was recently described to have a role in the development of the vomeronasal organ, where GnRH neurons originate (4).
These authors show that genetic invalidation of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulb. Pharmacological invalidation of the Notch signaling pathway impaired the motility of a murine immortalized GnRH cell line and of human fetal GnRH-secreting neuroblasts. In addition, the authors identified 9 heterozygous JAG1 mutations among 467 patients with congenital hypogonadotropic hypogonadism.
In conclusion, this study identified a role of Jag1/Notch signaling in the development of GnRH neurons and as new cause of congenital hypogonadotropic hypogonadism.
References: 1. Duittoz AH, Forni PE, Giacobini P, Golan M, Mollard P, Negrón AL, Radovick S, Wray S. Development of the gonadotropin-releasing hormone system. J. Neuroendocrinol. 2021;34(5):e13087. 2. Cangiano, B., Swee DS, Quinton R, Bonomi M. Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease. Hum. Genet. 2021;140:77–111. 3. Lasky JL, Wu H. Notch signaling, brain development, and human disease. Pediatr Res. 2005;57(7):104R–109R. 4. Katreddi RR, Taroc EZM, Hicks SM, Lin JM, Liu S, Xiang M, Forni PE. Notch signaling determines cell-fate specification of the two main types of vomeronasal neurons of rodents. Development. 2022;149(13):dev200448.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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