[show abstract][hide abstract] ABSTRACT: The early telencephalon shares molecular features with the early mid-hindbrain region. In particular, these two developing brain areas each have a signaling center that secretes FGFs and an adjacent one that secretes WNTs. WNTs and FGFs each play essential roles in regulating cell fates in both the telencephalon and mid-hindbrain. Despite this similarity, telencephalic and mid-hindbrain precursors express distinct genes and ultimately generate different cell types, tissue morphologies, and neural functions.
Here we show that genetically increasing the level of β-catenin, a mediator of canonical WNT signaling, in the anterior neural plate causes a loss of telencephalic characteristics and a gain of mid-hindbrain characteristics.
These results, together with previous ones demonstrating that increased WNT signaling in the anterior neural plate increases FGF expression, suggest that the levels of WNT and FGF signaling regulate telencephalic versus mid-hindbrain fates.
[show abstract][hide abstract] ABSTRACT: Growing evidence suggests that FGFs secreted from embryonic signaling centers are key mediators of cell survival. However, the mechanisms regulating FGF-dependent cell survival remain obscure. At the rostral end of the embryo, for example, ablation of FGF signaling leads to the rapid death of the precursor cells that form the anterior head, including the telencephalon. Here, we outline a core genetic circuit that regulates survival in the embryonic mouse head: WNT signaling through β-catenin directly maintains FGF expression and requires FGF function in vivo to oppose proapoptotic TGF-β signaling through SMAD4. Moreover, these antagonistic pathways converge on the transcriptional regulation of apoptosis, and genes such as Cdkn1a, suggesting a mechanism for how signaling centers in the embryonic head regulate cell survival.
[show abstract][hide abstract] ABSTRACT: The 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.
Development 04/2010; 137(10):1601-11. · 6.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: The FGF family of extracellular signaling factors has been proposed to play multiple roles in patterning the telencephalon, the precursor to the cerebrum. In this study, unlike previous ones, we effectively abolish FGF signaling in the anterior neural plate via deletion of three FGF receptor (FGFR) genes. Triple FGFR mutant mice exhibit a complete loss of the telencephalon, except the dorsal midline. Disruption of FGF signaling prior to and coincident with telencephalic induction reveals that FGFs promote telencephalic character and are strictly required to keep telencephalic cells alive. Moreover, progressively more severe truncations of the telencephalon are observed in FGFR single, double and triple mutants. Together with previous gain-of-function studies showing induction of Foxg1 expression and mirror-image duplications of the cortex by exogenous FGF8, our loss-of-function results suggest that, rather than independently patterning different areas, FGF ligands and receptors act in concert to mediate organizer activity for the whole telencephalon.
Development 08/2009; 136(14):2457-65. · 6.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sonic hedgehog (SHH) is required to generate ventral cell types throughout the central nervous system. Its role in directly specifying ventral cells, however, has recently been questioned because loss of the Shh gene has little effect on ventral development if the Gli3 gene is also mutant. Consequently, another ventral determinant must exist. Here, genetic evidence establishes that FGFs are required for ventral telencephalon development. First, simultaneous deletion of Fgfr1 and Fgfr3 specifically in the telencephalon results in the loss of differentiated ventromedial cells; and second, in the Fgfr1;Fgfr2 double mutant, ventral precursor cells are lost, mimicking the phenotype obtained previously with a loss of SHH signalling. Yet, in the Fgfr1;Fgfr2 mutant, Shh remains expressed, as does Gli1, the transcription of which depends on SHH activity, suggesting that FGF signalling acts independently of SHH to generate ventral precursors. Moreover, the Fgfr1;Fgfr2 phenotype, unlike the Shh phenotype, is not rescued by loss of Gli3, further indicating that FGFs act downstream of Shh and Gli3 to generate ventral telencephalic cell types.
Development 09/2006; 133(15):2937-46. · 6.21 Impact Factor