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)

From: A method to identify and analyze biological programs through automated reasoning

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.

  1. This suggests that these may be plausible missing connections in the network governing cardiac development.