Divergence of epidermal growth factor-transforming growth factorβ signaling in embryonic orofacial tissue
University of Louisville Birth Defects Center, Department of Molecular, Cellular and Craniofacial Biology, University of Louisville School of Dentistry, Louisville, Kentucky 40292, USA.In Vitro Cellular & Developmental Biology - Animal (Impact Factor: 1.15). 05/2003; 39(5-6):257-61. DOI: 10.1290/1543-706X(2003)039<0257:DOEGFG>2.0.CO;2
The epidermal growth factor (EGF) and transforming growth factor beta (TGFbeta) families of signaling molecules play a major role in growth and development of embryos. Abrogation of either signaling pathway results in defects in embryogenesis, including cleft palate. In the developing palate, both EGF and TGFbeta regulate cellular proliferation, extracellular matrix synthesis, and cellular differentiation but often in an opposing manner. Evidence from various adult cell types suggests the existence of cross talk between the EGF and TGFbeta signaling pathways, although it is unclear whether such cross talk exists in murine embryonic maxillary mesenchymal cells, from which the developing palate is derived. In this study, embryonic maxillary mesenchymal cells in culture were treated with EGF and TGFbeta, either singly or in combination, and the cells were subsequently examined for signaling interactions between these two pathways. Immunoblot analyses of nuclear extracts of embryonic maxillary mesenchymal cells revealed that TGFbeta-induced nuclear translocation of Smad 2 and Smad 3 proteins was not affected by EGF. Conversely, immunoblot analyses of whole-cell extracts of these cells indicated that EGF-induced phosphorylation of extracellular signal-regulated kinase proteins, ERK1 and ERK2, was not affected by TGFbeta. Expression of a transfected luciferase reporter gene driven by a promoter with Smad binding elements was induced by TGFbeta in these cells but was not affected by EGF. Last, TGFbeta was found to induce expression of the endogenous gelatinase B gene in embryonic maxillary mesenchymal cells; however, this effect was independent of any interaction of EGF. Collectively, data from this study suggest that the EGF and TGFbeta signal transduction pathways do not converge in murine embryonic maxillary mesenchymal cells.
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ABSTRACT: Despite the fact that orofacial clefts represent one of the most common birth defects, the molecular mechanisms by which the embryonic primordia of the midface grow and differentiate are not completely understood. A multiplicity of genes must be expressed and their protein products must interact in a highly orchestrated fashion to affect normal orofacial development. Several families of growth factors have emerged as key contributors to the choreography of cellular and tissue interactions contributing to morphogenesis of the orofacial region. This overview focuses on those growth factors that are generally accepted as playing a pivotal role in normal as well as abnormal development of first branchial arch-derived structures. Particular emphasis is given transforming growth factor-beta (TGF beta) and TGF alpha family members, as these have been the most extensively investigated with regard to their role in development of orofacial structures. Consideration is also given to evidence implicating developmental contributions from members of the bone morphogenetic protein and fibroblast growth factor families.
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ABSTRACT: Numerous signaling molecules have been shown to participate in the dynamic process of orofacial development. Among these signal mediators, members of the transforming growth factor beta (TGFbeta) superfamily have been shown to play critical roles. Developing orofacial tissue expresses TGFbeta and bone morphogenetic protein (BMP) mRNAs, their protein isoforms and TGFbeta- and BMP-specific receptors. All these molecules display unique temporospatial patterns of expression in embryonic orofacial tissue, suggesting functional roles in orofacial development. For example, the TGFbetas and BMPs regulate maxillary mesenchymal cell proliferation and extracellular matrix synthesis. This is particularly noteworthy in that perturbation of either process results in orofacial clefting. Although the cellular and phenotypic effects of the TGFbeta superfamily of growth factors on embryonic orofacial tissue have been extensively studied, the specific genes that function as effectors of these cytokines in orofacial development have not been well defined. In the present study, oligonucleotide-based microarray technology was utilized to provide a comprehensive analysis of the expression of the panoply of genes related to the TGFbeta superfamily, as well as those encoding diverse groups of proteins functionally associated with this superfamily, during orofacial ontogenesis. Of the 7000 genes whose expression was detected in the developing orofacial region, 249 have been identified that encode proteins related to the TGFbeta superfamily. Expression of some (27) of these genes was temporally regulated. In addition, several candidate genes, whose precise role in orofacial development is still unknown, were also identified. Examples of genes constituting this cluster include: TGFbeta1-induced antiapoptotic factor-1 and -2, TGFbeta-induced factor 2, TGFbeta1 induced transcript-1 and -4, TGFbeta-inducible early growth response 1, follistatin-like 1, follistatin-like 3, transmembrane protein with EGF-like and two follistatin-like domains (Tmeff)-1 and -2, nodal modulator 1, various isoforms of signal transducers and activators of transcription (Stat), notch, and growth and differentiation factors. Elucidation of the precise physiological roles of these proteins in orofacial ontogenesis should provide unique insights into the intricacies of the TGFbeta superfamily signal transduction pathways utilized during orofacial development.
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ABSTRACT: Arsenic is a ubiquitous element that is a potential carcinogen and teratogen and can cause adverse developmental outcomes. Arsenic exerts its toxic effects through the generation of reactive oxygen species (ROS) that include hydrogen peroxide (H(2)O(2)), superoxide-derived hydroxyl ion, and peroxyl radicals. However, the molecular mechanisms by which arsenic induces cytotoxicity in murine embryonic maxillary mesenchymal (MEMM) cells are undefined. MEMM cells in culture were treated with different concentrations of pentavalent sodium arsenate [As (V)] for 24 or 48 hr and various end points measured. Treatment of MEMM cells with the pentavalent form of inorganic arsenic resulted in caspase-mediated apoptosis, accompanied by generation of ROS and disruption of mitochondrial membrane potential. Treatment with caspase inhibitors markedly blocked apoptosis. In addition, the free radical scavenger N-acetylcysteine dramatically attenuated arsenic-mediated ROS production and apoptosis, and exposure to arsenate increased Bax and decreased Bcl protein levels in MEMM cells. Taken together, these findings suggest that in MEMM cells arsenate-mediated oxidative injury acts as an early and upstream initiator of the cell death cascade, triggering cytotoxicity, mitochondrial dysfunction, altered Bcl/Bax protein ratios, and activation of caspase-9.
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