Does the Dorsal Mesenchymal Protrusion Act as a Temporary Pacemaker during Heart Development?

Sun et al. (1) report that the dorsal mesenchymal protrusion (DMP) acts as a temporary pacemaker during early development, prior to formation of the atrioventricular node (AVN). We would like to question whether the anatomical designation of the DMP used in this paper is correct.The DMP was originally described as a mesenchymal protrusion from the dorsal mesocardium toward the atrial cavity contributing to the base of the atrial septum along with the mesenchymal cap and AV cushions (see Fig. 1) (2). To differentiate between the DMP prior to muscularization (which occurs from approximately embryonic day (E)13 in mouse) and other structures in the AV junction (AVJ) during early development, stainings of myocardial markers are essential, which are lacking in the paper by Sun et al. (1). In our opinion, the Shox2+ region described by Sun et al. (1) as DMP at E11.5 and E12.5 corresponds to CTNI+/HCN4+/ISL1+ cells of the putative AVN region and not the DMP (CTNI−/HCN4−/ISL1+) (see Fig. 1 and Refs. 3 and 4). HCN4 expression to date has not been described in mesenchyme (3,–5). Co-expression of HCN4/TBX3 in cells in the AVJ, with nodal-like electrophysiological characteristics (1) corresponds to the (putative) AVN region instead of the DMP, which is in accordance with our own observations (4). Misnaming the DMP during early development leads to the erroneous conclusion that this structure shows pacemaking properties.FIGURE 1.Description of structures in the atrioventricular junction at E11.5. Panels A–E show transverse sections just below the entrance of the pulmonary veins. A, overview of CTNI/HCN4/ISL1 staining. Boxed area is shown in B–E. B, merge of different ...Although we do not support the conclusion that the DMP acts as a temporary pacemaker, the results described by Sun et al. (1) elegantly show an important role for the Shox2-BMP pathway during AVN development.