title: The indirect role of fibroblast growth factor-8 in defining neurogenic niches of the olfactory/GnRH systems.
abstract: Bone morphogenic protein-4 (BMP4) and fibroblast growth factor-8 (FGF8) are thought to have opposite roles in defining epithelial versus neurogenic fate in the developing olfactory/vomeronasal system. In particular, FGF8 has been implicated in specification of olfactory and gonadotropin releasing hormone-1 (GnRH) neurons, as well as in controlling olfactory stem cell survival. Using different knock-in mouse lines and Cre-lox-mediated lineage tracing, Fgf8 expression and cell lineage was analyzed in the developing nose in relation to the expression of Bmp4 and its antagonist Noggin (Nog). FGF8 is expressed by cells that acquire an epidermal, respiratory cell fate and not by stem cells that acquire neuronal olfactory or vomeronasal cell fate. Ectodermal and mesenchymal sources of BMP4 control the expression of BMP/TGFβ antagonist Nog, whereas mesenchymal sources of Nog define the neurogenic borders of the olfactory pit. Fgf8 hypomorph mouse models, Fgf8(neo/neo) and Fgf8(neo/null), displayed severe craniofacial defects together with overlapping defects in the olfactory pit including (1) lack of neuronal formation ventrally, where GnRH neurons normally form, and (2) altered expression of Bmp4 and Nog, with Nog ectopically expressed in the nasal mesenchyme and no longer defining the GnRH and vomeronasal neurogenic border. Together our data show that (1) FGF8 is not sufficient to induce ectodermal progenitors of the olfactory pit to acquire neural fate and (2) altered neurogenesis and lack of GnRH neuron specification after chronically reduced Fgf8 expression reflected dysgenesis of the nasal region and loss of a specific neurogenic permissive milieu that was defined by mesenchymal signals.
authors: Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, Unit on Ocular and Stem Cell Translational Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, and Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.
authors: Paolo Emanuele
authors: PE
authors: Forni
authors: Kapil
authors: K
authors: Bharti
authors: Ellen M
authors: EM
authors: Flannery
authors: Tomomi
authors: T
authors: Shimogori
authors: Susan
authors: S
authors: Wray
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009833:Olfactory Pathways / Q000378:metabolism / Q000502:physiology*; D019147:Vomeronasal Organ / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C496457:Fgf8 protein, mouse; D051524:Fibroblast Growth Factor 8; D007987:Gonadotropin-Releasing Hormone