Opposing Fgf and Bmp activities regulate the specification of olfactory sensory and respiratory epithelial cell fates

Abstract

SUMMARYThe olfactory sensory epithelium and the respiratory epithelium are derived from the olfactory placode. However, the molecular mechanisms regulating the differential specification of the sensory and the respiratory epithelium have remained undefined. To address this issue, we first identified Msx1/2 and Id3 as markers for respiratory epithelial cells by performing quail chick transplantation studies. Next, we established chick explant and intact chick embryo assays of sensory/respiratory epithelial cell differentiation and analyzed two mice mutants deleted of Bmpr1a;Bmpr1b or Fgfr1;Fgfr2 in the olfactory placode. In this study, we provide evidence that in both chick and mouse, Bmp signals promote respiratory epithelial character, whereas Fgf signals are required for the generation of sensory epithelial cells. Moreover, olfactory placodal cells can switch between sensory and respiratory epithelial cell fates in response to Fgf and Bmp activity, respectively. Our results provide evidence that Fgf activity suppresses and restricts the ability of Bmp signals to induce respiratory cell fate in the nasal epithelium. In addition, we show that in both chick and mouse the lack of Bmp or Fgf activity results in disturbed placodal invagination; however, the fate of cells in the remaining olfactory epithelium is independent of morphological movements related to invagination. In summary, we present a conserved mechanism in amniotes in which Bmp and Fgf signals act in an opposing manner to regulate the respiratory versus sensory epithelial cell fate decision.

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

“…Tucker et al (2010) proposed that local FGF8 sources in the developing OP are responsible for specification and transition of primordial stem cells to terminally neurogenic precursors. However, the identity and location of these multipotent stem cells in the OP was still unclear Maier et al, 2010;Tucker et al, 2010). To follow neurogenesis and cell fate specification, the expression of neural and epidermal markers was analyzed with respect to expression of Fgf8.…”

“…To follow neurogenesis and cell fate specification, the expression of neural and epidermal markers was analyzed with respect to expression of Fgf8. SOX2 and PAX6 were used as stem/neural progenitor markers (Kawauchi et al, 2004), HuC/D was used as an early neuronal marker (Fornaro et al, 2003), while AP2␣, ID3, and MSX1 were used to identify epidermal cells Maier et al, 2010;Forni et al, 2011b). Analysis of knock-in mice expressing ␤-gal under direct control of Fgf8, Fgf8 nullLacZ /WT , confirmed that Fgf8 is expressed in the rostral portion of the invaginating OP [corresponding to the putative respiratory epithelium, (RE)], as well as in the epidermis proximal to the rim of the OP ( Fig.…”

“…Bmp4 is expressed in the mesenchyme proximal to Fgf8 sources BMP4 has been shown to suppress neurogenesis and to initiate an epidermal/RE differentiation program in progenitor cells in the nasal pit (Wilson and Hemmati-Brivanlou, 1995;Hu et al, 2008;Maier et al, 2011). Though opposite roles for FGF8 and BMP in controlling neurogenesis have been proposed (Maier et al, 2010), the spatial relation between the sources of these signals and their direct effect on neural induction in the OP is unclear .…”

“…Although fibroblast growth factor-8 (FGF8) signaling is thought to play a key role, together with bone morphogenic protein (BMP)/TGF␤ antagonists, in inducing neuronal cell fate (Wilson and Hemmati-Brivanlou, 1995;Zimmerman et al, 1996;Streit et al, 2000;Chmielnicki et al, 2004;Chiba et al, 2008;Marchal et al, 2009;Tang et al, 2009), the full role played by FGF, BMP, and BMP antagonists in controlling neurogenesis in cranial placodes is not entirely clear (Chung et al, 2008;Maier et al, 2010;Tucker et al, 2010). One example of a cranial placode-derived neuronal population is the GnRH neurons.…”

“…Defective FGF8 signaling in mice affects progenitor cell identity, olfactory neurogenesis, and GnRH cell fate specification (Riley et al, 2007;Chung et al, 2008;Falardeau et al, 2008;Chung and Tsai, 2010;Sabado et al, 2012). Developmental olfactory defects emerging after reduced FGF8 signal transduction have been previously interpreted as direct result of (1) progressive primordial stem cell death , (2) changes in precursor cell identity with expansion of uncommitted stem cells and loss of neurogenic progenitors (Tucker et al, 2010), or (3) decreased stem cells that access the neurogenic program with an increase in epidermal cell fate (Maier et al, 2010). However, the nature of these "primordial stem" cells is unclear and no one knows precisely how dysmorphic craniofacial devel-opment itself affects development of olfactory/GnRH neurogenesis in Fgf8 mutants.…”