PMC:1635039 / 3499-5886 JSONTXT

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In addition, recent studies have identified novel TGF-β-related ligands, which can bind to entire different combinations of receptors. For instance, growth and differentiation factors (GDFs) 8 and 9 can bind to Activin type II receptor and ALK5 to activate TGF-β Smads [17,18]. Therefore, we hypothesized that deletion of Alk5 in a specific cell lineage should reveal phenotypes which cannot be seen in comparable mutants lacking Tgfbr2. Indeed, we recently showed that neural crest cell specific Alk5 mutants display a unique spectrum of craniofacial developmental defects, e.g., cleft snout and severe mandibular hypoplasia [19]; these phenotypes were not seen in corresponding Tgfbr2 mutants [20]. To determine, whether ALK5 would also mediate unique non-redundant signaling events in cardiac neural crest cells, we focused on cardiac and pharyngeal phenotypes of mouse embryos lacking Alk5 specifically in neural crest cells. We discovered that in Alk5/Wnt1-Cre mutants, pharyngeal organs (thymus and parathyroid) fail to migrate appropriately. Moreover, the mutant embryos display severe aortic sac and pharyngeal arch artery defects, and failed aortico-pulmonary septation leading to PTA. Our data further suggest that at least some of these abnormal detected phenotypes result from a dramatic increase in apoptosis of postmigratory cardiac neural crest cells. These phenotypes differ remarkably from those seen in corresponding Tgfbr2 mutants, suggesting that ALK5 mediates a wider spectrum of signaling events than its classical binding partner TGFβRII in cardiac neural crest cells during cardiac and pharyngeal 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