Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome
| Autor: | Alessia Caramello, Alessandro Fantin, Kathryn Davidson, Sophie Chauvet, Pierre Bouloux, Daniele Cassatella, Fanny Mann, Valentina Andre, Christiana Ruhrberg, Anna Cariboni |
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| Přispěvatelé: | Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male endocrine system medicine.medical_specialty Neurite Kallmann syndrome Cell Adhesion Molecules Neuronal Nerve Tissue Proteins [SDV.BC]Life Sciences [q-bio]/Cellular Biology Gonadotropin-releasing hormone Semaphorins Biology Gonadotropin-Releasing Hormone 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Internal medicine medicine Animals Humans Exome Exome sequencing 030304 developmental biology Glycoproteins GnRH Neuron Neurons 0303 health sciences Membrane Glycoproteins Plexin Intracellular Signaling Peptides and Proteins Membrane Proteins General Medicine Kallmann Syndrome medicine.disease Mice Mutant Strains Cytoskeletal Proteins Endocrinology medicine.anatomical_structure Mutation biology.protein Commentary Neuron hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery Research Article Neurotrophin Signal Transduction |
| Zdroj: | Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2015, 125 (6), pp.2413-28. ⟨10.1172/JCI78448⟩ Journal of Clinical Investigation, 2015, 125 (6), pp.2413-28. ⟨10.1172/JCI78448⟩ |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/JCI78448⟩ |
| Popis: | International audience; Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1-dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency. |
| Databáze: | OpenAIRE |
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