ArticleThe Journal of clinical investigation2015
Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 114 citations in OpenAlex.
- Genetics of Idiopathic Hypogonadotropic HypogonadismJournal of clinical research in pediatric endocrinology · 2026Review
- CRISPR activation of DLX5 drives neural progenitors to the GnRH cell fate.Journal of molecular endocrinology · 2026Article
- Knockout of PI4-Kinase A in GnRH Neurons Causes their Prepubertal Death.bioRxiv : the preprint server for biology · 2026Article
- PI4-kinase A is essential for survival of the GnRH neurons.Frontiers in endocrinology · 2026Article
- Bilateral Testicular Regression Syndrome and Optic Nerve Atrophy: Clinical Aspects of a Child with a <italic>SEMA3E</italic> Loss-of-Function Variant.Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation · 2025Article
- Patient stratification by genetic risk in Alzheimer's disease is only effective in the presence of phenotypic heterogeneity.PloS one · 2025Article
- Age, sex, and cell type-resolved hypothalamic gene expression across the pubertal transition in mice.Biology of sex differences · 2024Article
- Methylome analysis in girls with idiopathic central precocious puberty.Clinical epigenetics · 2024Article
- Illuminating the terminal nerve: Uncovering the link between GnRH-1 neuron and olfactory development.The Journal of comparative neurology · 2024Article
- Increased burden of rare protein-truncating variants in constrained, brain-specific and synaptic genes in extremely impulsively violent males with antisocial personality disorder.Genes, brain, and behavior · 2024Article
- DigenicHeliyon · 2024Article
- SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability.Nature communications · 2023Article
- Clinical and molecular features of 40 Chinese patients with idiopathic hypogonadotropic hypogonadism.Translational andrology and urology · 2023Article
- Insulin-like Growth Factor 1, Growth Hormone, and Anti-Müllerian Hormone Receptors Are Differentially Expressed during GnRH Neuron Development.International journal of molecular sciences · 2023Article
- Defective jagged-1 signaling affects GnRH development and contributes to congenital hypogonadotropic hypogonadism.JCI insight · 2023Article
- Autism-linked NLGN3 is a key regulator of gonadotropin-releasing hormone deficiency.Disease models & mechanisms · 2023Article
- Article
- PlexinD1 signaling controls domain-specific dendritic development in newborn neurons in the postnatal olfactory bulb.Frontiers in neuroscience · 2023Article
- Mammalian puberty: a fly perspective.The FEBS journal · 2023Review
- A Novel Loss-of-FunctionInternational journal of molecular sciences · 2022Article
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Authors and funding
10 authors at 4 institutions in 3 countries.
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Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.