Table 3 Similarities and differences in parallel stages of cANS development at the venous pole in mice and humans

Early cardiogenesis

> Mice: E9.5–E11.5

> Human: 6–7 WGA

• Cardiac looping

• Sinus venosus U-shaped

• Atrial septation initiated

• NCC migration

• Sympathetic trunks and first mediastinal parasympathetic nerves discernable

• TUBB3⁺ cells in area of developing vagal nerves

• NCCs in the dorsal mesocardium at the area of the developing PV

• Absent parasympathetic cardiac ganglia

Mid cardiogenesis

> Mice: E12.5–E13.5

> Human: 8–9 WGA

• SAN formation established

• Venous valves formed

• Pulmonary vein canalized

• Start myocardialization of cardinal vein(s) and pulmonary vein

• First TUBB3⁺ nerves (co-expressing with ChAT) observed in the venous pole, entering near the developing PV

• Cardiac ganglia formation at orifice pulmonary vein and dorsal atrial wall

• TUBB3⁺ nerves distribute over the (SAN(s), proximal cardinal vein(s), dorsal atrial wall, pulmonary vein

• Only in humans, the left SAN and left superior caval vein disappear

• Only in mice, ICA cells appear in the right SAN

• In humans nerves have not differentiated yet (ChAT and TH negative) while in mice most nerves are ChAT⁺ and few TH⁺

Late cardiogenesis

> Mice: E15.5–E18.5

> Human: 10–20 WGA

• Major cardiogenesis is complete

• Increase of nerve distribution and density over venous pole

• Most nerves express both TH and ChAT at later developmental stages

• In mice, the left-sided SAN disappears now

• In mice, increase of ICA cells at the right-sided SAN, in human still absent