The canonical Wnt/ß-catenin signaling pathway regulates Fgf signaling for early facial development

Department of Cell Biology and Human Anatomy, University of California, Davis, Sacramento, CA 95817, USA.
Developmental Biology (Impact Factor: 3.55). 11/2010; 349(2):250-60. DOI: 10.1016/j.ydbio.2010.11.004
Source: PubMed


The canonical Wnt/β-catenin signaling pathway has implications in early facial development; yet, its function and signaling mechanism remain poorly understood. We report here that the frontonasal and upper jaw primordia cannot be formed after conditional ablation of β-catenin with Foxg1-Cre mice in the facial ectoderm and the adjacent telencephalic neuroepithelium. Gene expression of several cell-survival and patterning factors, including Fgf8, Fgf3, and Fgf17, is dramatically diminished in the anterior neural ridge (ANR, a rostral signaling center) and/or the adjacent frontonasal ectoderm of the β-catenin conditional mutant mice. In addition, Shh expression is diminished in the ventral telencephalon of the mutants, while Tcfap2a expression is less affected in the facial primordia. Apoptosis occurs robustly in the rostral head tissues following inactivation of Fgf signaling in the conditional mutants. Consequently, the upper jaw, nasal, ocular and telencephalic structures are absent, but the tongue and mandible are relatively developed in the conditional mutants at birth. Using molecular biological approaches, we demonstrate that the Fgf8 gene is transcriptionally targeted by Wnt/β-catenin signaling during early facial and forebrain development. Furthermore, we show that conditional gain-of-function of β-catenin signaling causes drastic upregulation of Fgf8 mRNA in the ANR and the entire facial ectoderm, which also arrests facial and forebrain development. Taken together, our results suggest that canonical Wnt/β-catenin signaling is required for early development of the mammalian face and related head structures, which mainly or partly acts through the initiation and modulation of balanced Fgf signaling activity.

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    • "The dorsomedial structures properly invaginate forming bifurcated lateral ventricles. Contrastingly, Foxg1-Cre-mediated deletion of ß-catenin in both dorsal neuroepithelial and mesenchymal cells, results in severe loss of midline telencephalic structures, failure of midline invagination and associated craniofacial defects [13], [14], [15]. The marked difference in phenotypic alterations in these two mutant lines may stem from the loss of ß-catenin signaling in mesenchymal cells in Foxg1-Cre;ß-catenin mutants. "
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    ABSTRACT: Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of ß-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of ß-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized ß-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that ß-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs) leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that ß-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis.
    PLoS ONE 02/2014; 9(2):e86025. DOI:10.1371/journal.pone.0086025 · 3.23 Impact Factor
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    • "Specifically, mesenchymal Isl1 is genetically upstream of the epithelial β-catenin–Fgf8 pathway in the hindlimb bud (Kawakami et al., 2011), while forelimb buds use another pathway, likely through Tbx5 (Agarwal et al., 2003; Rallis et al., 2003). Similar to the limb bud epithelium, the present study and recent studies demonstrated β-catenin regulation of Fgf8 in the epithelium of BA1 (Reid et al., 2011; Sun et al., 2012; Wang et al., 2011). Furthermore, ectopic activation of the β-catenin pathway in the facial epithelium was associated with surface thickening (Fig. S7). "
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    ABSTRACT: Isl1 expression marks progenitor populations in developing embryos. In this study, we investigated the contribution of Isl1-expressing cells that utilize the ß-catenin pathway to skeletal development. Inactivation of ß-catenin in Isl1-expressing cells caused agenesis of the hindlimb skeleton and absence of the lower jaw (agnathia). In the hindlimb, Isl1-lineages broadly contributed to the mesenchyme, however, deletion of ß-catenin in the Isl1-lineage caused cell death only in a discrete posterior domain of nascent hindlimb bud mesenchyme. We found that the loss of posterior mesenchyme, which gives rise to Shh-expressing posterior organizer tissue, caused loss of posterior gene expression and failure to expand chondrogenic precursor cells, leading to severe truncation of the hindlimb. In facial tissues, Isl1-expressing cells broadly contributed to facial epithelium. We found reduced nuclear ß-catenin accumulation and loss of Fgf8 expression in mandibular epithelium of Isl1(-/-) embryos. Inactivating ß-catenin in Isl1-expressing epithelium caused both loss of epithelial Fgf8 expression and death of mesenchymal cells in the mandibular arch without affecting epithelial proliferation and survival. These results suggest a Isl1->ß-catenin->Fgf8 pathway that regulates mesenchymal survival and development of the lower jaw in the mandibular epithelium. By contrast, activating ß-catenin signaling in Isl1-lineages caused activation of Fgf8 broadly in facial epithelium. Our results provide evidence that, despite its broad contribution to hindlimb mesenchyme and facial epithelium, the Isl1-ß-catenin pathway regulates skeletal development of the hindlimb and lower jaw through discrete populations of cells that give rise to Shh-expressing posterior hindlimb mesenchyme and Fgf8-expressing mandibular epithelium.
    Developmental Biology 01/2014; 387(1). DOI:10.1016/j.ydbio.2014.01.001 · 3.55 Impact Factor
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    • "lined with yellow dashed arrow; Crossley et al., 2001; Wang et al., 2011). The disappearance is spatiotemporally correlated with the pattern of apoptosis in the ANR (Figures 2H and 2K). "
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    ABSTRACT: Apoptotic cells are observed in the early developing brain. Apoptosis deficiency is proposed to cause brain overgrowth, but here we show that brain malformations in apoptosis-deficient mutants are due to insufficient brain ventricle expansion as a result of uncompleted cranial neural tube closure. Apoptosis eliminates Fgf8-expressing cells in the anterior neural ridge (ANR), which acts as an organizing center of the forebrain by producing FGF8 morphogen. Deficiency of apoptosis leads to the accumulation of undead and nonproliferative cells in the ventral part of the ANR. The undead cells in apoptosis-deficient mutants express Fgf8 continuously, which perturbs gene expression in the ventral forebrain. Thus, apoptosis within a specific subdomain of the ANR is required for correct temporal elimination of an FGF8-producing region within a limited developmental time window, thereby ensuring proper forebrain development.
    Developmental Cell 12/2013; 27(6):621-34. DOI:10.1016/j.devcel.2013.11.015 · 9.71 Impact Factor
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