FGF Signaling Regulates the Number of Posterior Taste Papillae by Controlling Progenitor Field Size

Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, California, USA.
PLoS Genetics (Impact Factor: 7.53). 06/2011; 7(6):e1002098. DOI: 10.1371/journal.pgen.1002098
Source: PubMed


The sense of taste is fundamental to our ability to ingest nutritious substances and to detect and avoid potentially toxic ones. Sensory taste buds are housed in papillae that develop from epithelial placodes. Three distinct types of gustatory papillae reside on the rodent tongue: small fungiform papillae are found in the anterior tongue, whereas the posterior tongue contains the larger foliate papillae and a single midline circumvallate papilla (CVP). Despite the great variation in the number of CVPs in mammals, its importance in taste function, and its status as the largest of the taste papillae, very little is known about the development of this structure. Here, we report that a balance between Sprouty (Spry) genes and Fgf10, which respectively antagonize and activate receptor tyrosine kinase (RTK) signaling, regulates the number of CVPs. Deletion of Spry2 alone resulted in duplication of the CVP as a result of an increase in the size of the placode progenitor field, and Spry1(-/-);Spry2(-/-) embryos had multiple CVPs, demonstrating the redundancy of Sprouty genes in regulating the progenitor field size. By contrast, deletion of Fgf10 led to absence of the CVP, identifying FGF10 as the first inductive, mesenchyme-derived factor for taste papillae. Our results provide the first demonstration of the role of epithelial-mesenchymal FGF signaling in taste papilla development, indicate that regulation of the progenitor field size by FGF signaling is a critical determinant of papilla number, and suggest that the great variation in CVP number among mammalian species may be linked to levels of signaling by the FGF pathway.

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Available from: Cyril Charles, Oct 08, 2015
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    • "Sprouty proteins are known as general inhibitors of RTKs with pleiotropic roles within development. Here, we have used Spry1 −/− ; Spry2 −/− double mutant embryos as a model for increased FGF- ERK signaling (Petersen et al., 2011). However, we cannot exclude the possibility that other RTKs can also stimulate ERK signaling in these mutant mice. "
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    • "Sprouty proteins are known as general inhibitors of RTKs with pleiotropic roles within development. Here, we have used Spry1 −/− ; Spry2 −/− double mutant embryos as a model for increased FGF- ERK signaling (Petersen et al., 2011). However, we cannot exclude the possibility that other RTKs can also stimulate ERK signaling in these mutant mice. "
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    ABSTRACT: The transition between the proliferation and differentiation of progenitor cells is a key step in organogenesis, and alterations in this process can lead to developmental disorders. The extracellular signal-regulated kinase 1/2 (ERK) signaling pathway is one of the most intensively studied signaling mechanisms that regulates both proliferation and differentiation. How a single molecule (e.g. ERK) can regulate two opposing cellular outcomes is still a mystery. Using both chick and mouse models, we shed light on the mechanism responsible for the switch from proliferation to differentiation of head muscle progenitors and implicate ERK subcellular localization. Manipulation of the fibroblast growth factor (FGF)-ERK signaling pathway in chick embryos in vitro and in vivo demonstrated that blockage of this pathway accelerated myogenic differentiation, whereas its activation diminished it. We next examined whether the spatial subcellular localization of ERK could act as a switch between proliferation (nuclear ERK) and differentiation (cytoplasmic ERK) of muscle progenitors. A myristoylated peptide that blocks importin 7-mediated ERK nuclear translocation induced robust myogenic differentiation of muscle progenitor/stem cells in both head and trunk. In the mouse, analysis of Sprouty mutant embryos revealed that increased ERK signaling suppressed both head and trunk myogenesis. Our findings, corroborated by mathematical modeling, suggest that ERK shuttling between the nucleus and the cytoplasm provides a switch-like transition between proliferation and differentiation of muscle progenitors.
    Development 06/2014; 141(13). DOI:10.1242/dev.107078 · 6.46 Impact Factor
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    • "Although Sox2 has not yet been reported as a WT1 target gene, it is possible that there is some level of connection between these factors in the developing CV papillae. CV papillae formation depends on a balance of expression between Sprouty and FGF genes, which regulate receptor tyrosine kinase signaling to control the number of CV papillae formed (Petersen et al., 2011). Whether there is any relationship between these genes and WT1 expression is currently unknown, but since loss of WT1 expression causes aberrant CV formation, it would be interesting to investigate the potential relationship between these signaling molecules. "
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    ABSTRACT: Despite the importance of taste in determining nutrient intake, our understanding of the processes that control the development of the peripheral taste system is lacking. Several early regulators of taste development have been identified, including sonic hedgehog, bone morphogenetic protein 4 and multiple members of the Wnt/β-catenin signaling pathway. However, the regulation of these factors, including their induction, remains poorly understood. Here, we identify a crucial role for the Wilms' tumor 1 protein (WT1) in circumvallate (CV) papillae development. WT1 is a transcription factor that is important in the normal development of multiple tissues, including both the olfactory and visual systems. In mice, WT1 expression is detectable by E12.5, when the CV taste placode begins to form. In mice lacking WT1, the CV fails to develop normally and markers of early taste development are dysregulated compared with wild type. We demonstrate that expression of the WT1 target genes Lef1, Ptch1 and Bmp4 is significantly reduced in developing tongue tissue derived from Wt1 knockout mice and that, in normal tongue, WT1 is bound to the promoter regions of these genes. Moreover, siRNA knockdown of WT1 in cultured taste cells leads to a reduction in the expression of Lef1 and Ptch1. Our data identify WT1 as a crucial transcription factor in the development of the CV through the regulation of multiple signaling pathways that have established roles in the formation and patterning of taste placodes.
    Development 05/2014; 141(11). DOI:10.1242/dev.105676 · 6.46 Impact Factor
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