The Indirect Role of Fibroblast Growth Factor-8 in Defining Neurogenic Niches of the Olfactory/GnRH Systems.

Bone morphogenic protein-4 (BMP4) and fibroblast growth factor-8 (FGF8) are thought to have opposite roles in defining epithe-lial versus neurogenic fate in the developing olfactory/vomeronasal system. In particular, FGF8 has been implicated in specifica-tion 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, Fgf8neo/neo and Fgf8neo/neo, displayed severe cranio-facial 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 Nogectopically 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 specifi-cation after chronically reduced Fgf8 expression reflected dysgenesis of the nasal region and loss of a specific neurogenic permis-sive milieu that was defined by mesenchymal signals. [ABSTRACT FROM AUTHOR]