Table 3. Through literature search, we found evidence to support six out of the eight new potential interactions identified that enable the temporal dynamics of differentiation to be satisfied (Figure 5c,d).
| Interaction | Experimental evidence |
|---|---|
| Nkx2.5 --> canWnt | Cambier et al.26 show that Nkx2.5 regulates cardiac growth, activating Wnt through induction of R-Spondin3, a positive regulator of canonical Wnt. |
| Mesp1 --| canWnt | David et al.27 show that Mesp1 induces DKK, an inhibitor of canonical Wnt signaling during cardiovascular differentiation (Mesp1 --> Dkk1 --| cantWnt). |
| GATAs --> canWnt | Afouda et al.28 show that inhibition of Gata4 and Gata6 results in reduced expression of cardiac markers and Wnt11. |
| Bmp2 --> canWnt | Papathanasiou et al.29 show that BMP2 activates canonical Wnt signaling through induction of LRP-5, a Wnt co-receptor. Rosen30 reviews results showing that, in bone development, Bmp2 knockout leads to downregulation of several Wnt pathway components and targets. |
| Foxc1/2 --| Tbx5 | Hilton et al.31 show that there may be an indirect regulation via Pitx2. |
| Foxc1/2 --> canWnt | Seo and Kume32 show that Wnt expression is absent in Foxc1−/−; Foxc2−/− compound mutants. |
This suggests that these may be plausible missing connections in the network governing cardiac development.