Connective Tissue Growth Factor (CTGF) Ablation Impairs Palatal Mesenchyme Growth
Joseph T. Tarr, B.S.1, Alex G. Lambi, M.D., Ph.D.2, Tim G. Visser, B.S.1, Steven N. Popoff, Ph.D.1, James P. Bradley, M.D.2.
1Temple University School of Medicine, Philadelphia, PA, USA, 2Temple University Hospital, Philadelphia, PA, USA.
Background: Nonsyndromic cleft palate is the most common craniofacial birth defect. Despite its high incidence, our understanding of its etiology remains poor. To date, multiple mouse models (TGF-beta-3 KO, IRF-6 KO) have been utilized, but have been limited by varying penetrance and severity. We have previously identified CTGF KO mice as a novel model to study cleft palate development.
Methods: CTGF KO and WT palates were isolated and grown in explant cultures. Histologic analyses were performed on explants at various time points. Next, mesenchymal cells were isolated from CTGF KO and WT palates and compared for cellular organization, proliferation, and migration. mRNA from palatal tissues was isolated and analyzed for alterations in known palatogenesis signaling pathways.
Results: Palatal explant cultures demonstrated that CTGF KO palates fail to grow horizontally and fuse compared to WT shelves. Additionally, when artificially approximated in culture, CTGF KO palates remain clefted. Mesenchymal cells isolated from palatal shelves demonstrate decreased proliferation, and altered migration, adhesion, and spreading. Abrogation in BMP, TGF-beta, FGF, and Wnt signaling pathways are seen in CTGF KO cells.
Conclusions: Defects in palatal mesenchyme growth contribute to the cleft palate phenotype of CTGF KO mice. Multiple signaling pathways necessary for normal palate development are affected by CTGF ablation. Our explant model is being used to elucidate the key mechanism(s) responsible for cleft palate in CTGF KO mice. These studies will further our understanding of cleft etiology and may elucidate novel therapeutic targets for clinical management of this birth defect.
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