Abstract
In vertebrate olfactory epithelium (OE), neurogenesis proceeds continuously, suggesting that endogenous signals support survival and proliferation of stem and progenitor cells. We used a genetic approach to test the hypothesis that Fgf8 plays such a role in developing OE. In young embryos, Fgf8 RNA is expressed in the rim of the invaginating nasal pit (NP), in a small domain of cells that overlaps partially with that of putative OE neural stem cells later in gestation. In mutant mice in which the Fgf8 gene is inactivated in anterior neural structures, FGF-mediated signaling is strongly downregulated in both OE proper and underlying mesenchyme by day 10 of gestation. Mutants survive gestation but die at birth, lacking OE, vomeronasal organ (VNO), nasal cavity, forebrain, lower jaw, eyelids and pinnae. Analysis of mutants indicates that although initial NP formation is grossly normal, cells in the Fgf8-expressing domain undergo high levels of apoptosis, resulting in cessation of nasal cavity invagination and loss of virtually all OE neuronal cell types. These findings demonstrate that Fgf8 is crucial for proper development of the OE, nasal cavity and VNO, as well as maintenance of OE neurogenesis during prenatal development. The data suggest a model in which Fgf8 expression defines an anterior morphogenetic center, which is required not only for the sustenance and continued production of primary olfactory (OE and VNO) neural stem and progenitor cells, but also for proper morphogenesis of the entire nasal cavity.
Highlights
Members of the fibroblast growth factor (FGF) superfamily of signaling molecules have important effects on cell proliferation, developmental patterning, cell growth and homeostasis in virtually all tissues in higher vertebrates (Ornitz, 2000)
To understand how Fgf8 might act to regulate olfactory epithelium (OE) neurogenesis, we first performed in situ hybridization for Fgf8 [using a probe encompassing the entire open reading frame (ORF) of the cDNA; see Materials and methods] and OE neuronal lineage markers on serial sections of invaginating nasal pit (NP) at day 10 of gestation (E10.5)
Expression of different OE neuronal cell typespecific markers occurs in an outside-in pattern that reflects the stage of each expressing cell in the neuronal lineage: cells expressing Mash1, which marks the earliest committed neuronal progenitors, are present next to the Fgf8-expressing cells at the inner rim of the NP; adjacent to Mash1-expressing cells are Ngn1-expressing INPs; and in the center of the pit lie cells that are positive for Ncam1
Summary
Members of the fibroblast growth factor (FGF) superfamily of signaling molecules have important effects on cell proliferation, developmental patterning, cell growth and homeostasis in virtually all tissues in higher vertebrates (Ornitz, 2000). Studies in vitro and in vivo have shown that FGFs promote proliferation, differentiation and survival of most neural cell types, including stem cells and neuronal progenitors (DeHamer et al, 1994; Eckenstein, 1994; Ford-Perriss et al, 2001; Reuss and von Bohlen und Halbach, 2003; Temple and Qian, 1995). FGF8 in particular appears to play an important role in developing nervous system, the mechanism(s) by which it acts have not been elucidated fully. The idea has emerged that FGF8 is involved in survival and/or maintenance of specific developing cell populations that give rise to particular components of the nervous system (Chi et al, 2003; Mathis et al, 2001; Storm et al, 2003)
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