Our present results suggest that while TGF-β signaling in cardiac NCCs is predominantly mediated via the ALK5/TGF-βRII receptor complex, ALK5 also mediates signaling of other related ligands, which are either directly or indirectly required for appropriate NCC survival. In fact, it has been shown that, besides TGF-βRII, ALK5 can also form a complex with the Activin type IIB receptor to activate downstream Smads 2/3 [18,31]. Furthermore, a subset of TGF-β-related growth and differentiation factors (GDFs), e.g., GDF8, GDF9, GDF11 and GDF15 could induce these events [17,18,32,33]. Although relevant Gdfs 8, 9 11 and 15 are not expressed in the developing heart, nor do the mice deficient in these Gdfs display developmental cardiac defects, we cannot exclude the possibility that circulating GDFs, perhaps in concert with TGF-βs may contribute to NCC survival during cardiac and pharyngeal morphogenesis.