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ZBTB20 mutations cause GnRH deficiency by impairing the neurogenesis in the subventricular zone

ABSTRACT: Background: Congenital hypogonadotropic hypogonadism (CHH) is caused by defective GnRH neuron development, yet nearly 50% of cases lack a genetic diagnosis, severely limiting clinical management. Since olfactory bulb (OB) malformations can disrupt GnRH neuron migration, we investigated whether impaired subventricular zone (SVZ) neurogenesis - critical for OB development - contributes to CHH pathogenesis. Methods: Leveraging our 15-year effort in building one of Asia’s largest CHH cohort (812 unrelated patients, 49 families), we identified a pathogenic ZBTB20 mutation (p.R300C) in a four-generation CHH family with 7 affected members that presents a unique opportunity to study disease mechanisms. We generated nervous system-specific Zbtb20 conditional knockout mice (cKO) to assess phenotypic and mechanistic consequences. Molecular analyses, including transcriptional regulation assays, were performed to explore downstream pathways. Findings: Four additional heterozygous ZBTB20 variants were detected in the CHH cohort. Zbtb20 cKO mice exhibited hallmark CHH features: GnRH neuron deficiency, hypogonadism, and infertility. Mechanistically, Zbtb20 deficiency impaired SVZ NSCs proliferation and disrupted their migration via the rostral migratory stream (RMS) to the OB. We identified Thbs4 as a key downstream target, as ZBTB20 transcriptionally activates Thbs4, which is critical for SVZ NSCs migration. Interpretation: Our study establishes ZBTB20 as a novel CHH-associated gene and demonstrates its essential role in SVZ-OB neurogenesis. Loss of ZBTB20 function leads to OB atrophy, GnRH deficiency, and CHH pathogenesis, uncovering a previously unrecognized link between SVZ NSCs dysregulation and reproductive neuroendocrine dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE308208 | GEO | 2026/03/31

REPOSITORIES: GEO

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Project description:The olfactory sensory system is formed by the coordinated morphogenesis and differentiation of the peripheral olfactory epithelium (OE) and the anterior forebrain. At early stages, immature olfactory receptor neurons (ORN) elongate their axons to penetrate the brain basement membrane, contact and form synapses with projection neurons of the olfactory bulb primordium. Axonal elongation is accompanied by migration of the GnRH+ neurons, followed by their ingression in the septo-hypothalamic area of the forebrain. This process is specifically impaired in the KallmannM-bM-^@M-^Ys syndrome (KS), a disorder characterized by anosmia and central hypogonadism. A set of transcription factors are master regulators of olfactory connectivity and GnRH neuron migration. We explored the transcriptional network underlying this process, by profiling the OE and adjacent mesenchyme at distinct embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene essential for olfactory development, that causes a KS-like phenotype when deleted. We also applied analysis of conserved co-expression to integrate the obtained data with information on KS disease genes. The prevalent categories of genes differentially expressed during development are neuronal differentiation, extracellular remodelling and cell adhesion. From the analysis of Dlx5 mutant tissues we identify about 120 genes with a prevalence of intermediate filaments, cell signalling, epithelial and neuronal differentiation. Filtering for true OE expression and for the presence of Dlx5 binding sites, yielded twenty genes, of the following categories: 1) transmembrane adhesion/receptor molecules, 2) axon-glia interaction molecules, 3) synaptic proteins, 4) scaffold/adapter for signalling molecules. To functionally analyze these genes in vivo, we used three zebrafish fluorescent reporter zebrafish strains, in which we monitored early phases of olfactory/GnRH development upon gene downmodulation. The depletion of three (of five) Dlx5 targets affected axonal extension and targeting, while two (of two) altered GnRH neuron position and neurite organization. In one experiment we compare the olfactrory sensory epithelium from wild-type embryos, at three times of development, i.e. E11.5, E12.5 and E14.5. In a second experiment we compare the olfactory sensory epithelium from wild-type embryo with that from Dlx5 knock-out embryos, at the age E12.5

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ZBTB20 mutations cause GnRH deficiency by impairing the neurogenesis in the subventricular zone

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