title: Profiling, Bioinformatic, and Functional Data on the Developing Olfactory/GnRH System Reveal Cellular and Molecular Pathways Essential for This Process and Potentially Relevant for the Kallmann Syndrome.
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.
authors.affiliation: Department of Molecular Biotechnology and Health Science, University of Torino , Torino , Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Garaffo
authors.affiliation: Department of Molecular Biotechnology and Health Science, University of Torino , Torino , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Department of Molecular Biotechnology and Health Science, University of Torino , Torino , Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Molineris
authors.affiliation: Department of Medical Biotechnology Translational Medicine (BIOMETRA), University of Milano , Milano , Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pinciroli
authors.affiliation: Institute of Biomedical Technology, National Research Council, ITB-CNR , Segrate , Italy.
authors.forename: Clelia
authors.initials: C
authors.lastname: Peano
authors.affiliation: Department of Medical Biotechnology Translational Medicine (BIOMETRA), University of Milano , Milano , Italy ; Institute of Biomedical Technology, National Research Council, ITB-CNR , Segrate , Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Battaglia
authors.affiliation: Department of Molecular Biotechnology and Health Science, University of Torino , Torino , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tomaiuolo
authors.affiliation: The George S. Wise Faculty of Life Sciences, Department of Neurobiology, Tel-Aviv University , Tel-Aviv , Israel.
authors.forename: Talya
authors.initials: T
authors.lastname: Etzion
authors.affiliation: The George S. Wise Faculty of Life Sciences, Department of Neurobiology, Tel-Aviv University , Tel-Aviv , Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gothilf
authors.affiliation: Department of Molecular Biotechnology and Health Science, University of Torino , Torino , Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.affiliation: Department of Molecular Biotechnology and Health Science, University of Torino , Torino , Italy.
authors.forename: Giorgio R
authors.initials: GR
authors.lastname: Merlo
keywords: GnRH neuron; Kallmann syndrome; disease gene prediction; extracellular matrix; olfactory development; transcription profiling