Abstract
During embryonic development, immature neurons in the olfactory epithelium (OE) extend axons through the nasal mesenchyme, to contact projection neurons in the olfactory bulb. Axon navigation is accompanied by migration of the GnRH+ neurons, which enter the anterior forebrain and home in the septo-hypothalamic area. This process can be interrupted at various points and lead to the onset of the Kallmann syndrome (KS), a disorder characterized by anosmia and central hypogonadotropic hypogonadism. Several genes has been identified in human and mice that cause KS or a KS-like phenotype. In mice a set of transcription factors appears to be required for olfactory connectivity and GnRH neuron migration; thus we explored the transcriptional network underlying this developmental process by profiling the OE and the adjacent mesenchyme at three embryonic ages. We also profiled the OE from embryos null for Dlx5, a homeogene that causes a KS-like phenotype when deleted. We identified 20 interesting genes belonging to the following categories: (1) transmembrane adhesion/receptor, (2) axon-glia interaction, (3) scaffold/adapter for signaling, (4) synaptic proteins. We tested some of them in zebrafish embryos: the depletion of five (of six) Dlx5 targets affected axonal extension and targeting, while three (of three) affected GnRH neuron position and neurite organization. Thus, we confirmed the importance of cell–cell and cell-matrix interactions and identified new molecules needed for olfactory connection and GnRH neuron migration. Using available and newly generated data, we predicted/prioritized putative KS-disease genes, by building conserved co-expression networks with all known disease genes in human and mouse. The results show the overall validity of approaches based on high-throughput data and predictive bioinformatics to identify genes potentially relevant for the molecular pathogenesis of KS. A number of candidate will be discussed, that should be tested in future mutation screens.
Highlights
Central Hypogonadic Hypogonadism (CHH), is a heterogeneous genetic disorders characterized by absent or incomplete puberty, due to low circulating gonadotropins and sex steroids
In mice a set of transcription factors appears to be required for olfactory connectivity and GnRH neuron migration; we explored the transcriptional network underlying this developmental process by profiling the olfactory epithelium (OE) and the adjacent mesenchyme at three embryonic ages
Mutations affecting a large number of unrelated genes have been linked to the onset of Kallmann syndrome (KS)/nCHH, currently including Anosmin1 (KAL1), Fibroblast Growth Factor Receptor-1 (FGFR1), Fibroblast Growth Factor 8 (FGF8), GnRH receptor (GNRH-R), Nasal Embryonic LHRH Factor (NELF), Kisspeptin (KISS1); Kisspeptin Receptor (KISS-R)/G-protein-Coupled Receptor 54 (GPR54), Prokineticin-2 (PROK-2), Prokineticin Receptor2 (PROKR2), Chromodomain Helicase DNA-binding Protein 7 (CHD7), Neurokinin-B (TAC3), Neurokinin-B Receptor (TAC3R), Heparan Sulfate 6-O-SulphoTransferase 1 (HS6ST1), SOX10, www.frontiersin.org
Summary
Central Hypogonadic Hypogonadism (CHH), is a heterogeneous genetic disorders characterized by absent or incomplete puberty, due to low circulating gonadotropins and sex steroids. Its mode of inheritance can be X-linked, autosomal dominant, or autosomal recessive, unrelated sporadic cases occur more frequently [1]. The disease is often associated with anosmia/hyposmia, in this case it is known as Kallmann Syndrome [KS, on-line Mendelian inheritance in man (OMIM) 308700], or with a normal sense of smell (normosmic CHH, or nCHH). These conditions are variably associated with non-reproductive phenotypes such as unilateral renal agenesis, skeletal abnormalities, midline malformations, or hearing loss. Neurological symptoms (including synkinesia of the hands, sensorineural deafness, eye-movement abnormalities, cerebellar ataxia, and gaze-evoked horizontal nystagmus) may occur depending on the specific mode of inheritance [2]. Mutations affecting a large number of unrelated genes have been linked to the onset of KS/nCHH, currently including Anosmin (KAL1), Fibroblast Growth Factor Receptor-1 (FGFR1), Fibroblast Growth Factor 8 (FGF8), GnRH receptor (GNRH-R), Nasal Embryonic LHRH Factor (NELF), Kisspeptin (KISS1); Kisspeptin Receptor (KISS-R)/G-protein-Coupled Receptor 54 (GPR54), Prokineticin-2 (PROK-2), Prokineticin Receptor (PROKR2), Chromodomain Helicase DNA-binding Protein 7 (CHD7), Neurokinin-B (TAC3), Neurokinin-B Receptor (TAC3R), Heparan Sulfate 6-O-SulphoTransferase 1 (HS6ST1), SOX10, www.frontiersin.org
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