(A) Schematic representation of cardiopharyngeal lineage cells at successive time points representing the main fate transitions. hpf: hours post-fertilization; TVC: trunk ventral cells; L: Leader T: trailer; migr.: migration; STVC: second trunk ventral cells; FHP: first heart precursors; dotted line: midline; black bars link sister cells; ASMF: atrial siphon muscle founder cells; SHP: second heart precursors; iASMP: inner atrial siphon muscle precursors; oASMP: outer atrial siphon muscle precursor (these cells correspond to stem-cell-like Mrf-; Notch+ precursors and Mrf+; Notch- differentiating myoblasts, respectively; see (Razy-Krajka et al., 2014) for details). (B) Lineage diagram and documented regulatory relationships between indicated genes and pathways, as showing here and in (Razy-Krajka et al., 2014; Wang et al., 2013). In TVCs, primed heart and ASM markers are coexpressed, and maintenance of the STVC and ASM markers requires ongoing FGF/MAPK signaling. Following the first oriented and asymmetric cell division, FGF-MAPK is maintained only in the STVCs, which permits the continued expression of Hand-r and the activation of Tbx1/10. Cell division, presumably through G1-specific inputs, contributes to Tbx1/10 activation, and Tbx1/10 function antagonizes Gata4/5/6 expression (Wang et al., 2013). In the FHPs, termination of FGF-MAPK signaling inhibits Hand-r expression and prevents Tbx1/10 activation. Following oriented and asymmetric division of the STVCs, FGF/MAPK signaling persists only in the ASMFs, where it permits the transient maintenance of Hand-r and Tbx1/10, both of which act in parallel to FGF/MAPK to activate Ebf expression, together with contributions from presumed G1 inputs. Ebf activities further antagonize the cardiac program (marked by Gata4/5/6, Nk4/Nkx2.5 and Hand expression; [Razy-Krajka et al., 2014; Stolfi et al., 2010; Wang et al., 2013]). Once Ebf expression reaches ‘high levels’, its regulation becomes MAPK-independent and self-activating (this study). It also feeds back negatively on early activators such as Hand-r, and promotes the expression of the muscle determinant Mrf (Razy-Krajka et al., 2014; Tolkin and Christiaen, 2016). We propose that this transition represents commitment to an ASM fate. In the SHPs, termination of FGF/MAPK signaling prevents maintenance of Hand-r and Tbx1/10 expression, which, together with repressive inputs from Nk4/Nkx2.5, inhibits Ebf activation (Wang et al., 2013), and permits heart fate specification (Wang et al., 2017).