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The handle http://hdl.handle.net/1887/58994 holds various files of this Leiden University dissertation.
Author: Kelder, T.P.
Title: The developing heartbeat: tracing and characterization of the developing cardiac conduction system
Issue Date: 2018-01-18
LETTER TO EDITOR:
DOES THE DORSAL MESENCHYMAL PROTRUSION ACT AS A TEMPORARY
PACEMAKER DURING HEART DEVELOPMENT?
Tim P. Kelder, Rebecca Vicente-Steijn, Marco C. DeRuiter, Adriana C. Gittenberger-de Groot, Monique R.M. Jongbloed.
Modified after Journal of Biological Chemistry, 290:
8013-4 (2015)
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DMP and AVN development 113
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LETTER TO EDITOR
Sun et al. report that the dorsal mesenchymal protrusion (DMP) acts as a temporary pacemaker during early development, prior to formation of the atrioventricular node (AVN).1 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 towards the atrial cavity contributing to the base of the atrial septum along with the mesenchymal cap and atrioventricular (AV) cushions (see Fig. 1).2 To differentiate between the DMP prior to muscularization (from approximately embryonic day (E)13 in mouse), and other structures in the AV junction during early development, stainings of myocardial markers are essential, which are lacking in the Sun paper.1 In our opinion, the Shox2+ region described by Sun et al. 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 refs3,4). HCN4 expression to date has not been described in mesenchyme.3–5 Co-expression of HCN4/TBX3 in cells in the AV junction, with nodal-like electrophysiological characteristics1 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.
Although we do not support the conclusion that the DMP acts as a temporary pacemaker, the results described by Sun et al. elegantly show an important role for the Shox2-BMP pathway during AVN development.
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Figure 1. 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 channels showing the HCN4-/CTNI-/ISL1+ DMP (arrowhead) protruding from the dorsal mesocardium (DM) towards the atrial cavity. The close relation with the mesenchymal cap (MC) is shown. C-E. Separate grey values of CTNI (C), HCN4 (D), and ISL1 (E). Panels F-J show transverse sections at the level of the base of the atrial septum, more caudal to the level shown in panels A-E. F. Overview, with boxed region shown in G-J. G. the HCN4-/CTNI-/ISL1+ (low expression of ISL1 at this level) DMP (arrowhead) is continuous with the MC, which in turn is continuous with the inferior atrioventricular cushion (iAVC). The arrow indicates the HCN4+/CTNI+/ISL1+ region designated by Sun et al. as DMP. However, co-expression of markers and the location directly above the iAVC at the base of the right atrium shows that this region corresponds to the region of the future AVN. H-J. grey values of CTNI (H), HCN4 (I), and ISL1 (J). Scalebar in A and F 100µm, other panels 50µm. AS: atrial septum, CTNI: cardiac troponin-I, HCN4:
hyperpolarization-activated cyclic nucleotide-gated channel 4, ISL1: Islet1, L/RCV: left/right cardinal vein, L/RV: left/right ventricle, L/RVV: left/right venous valve, RA: right atrium, sAVC: superior atrioventricular cushion.
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REFERENCE LIST
1. Sun, C. et al. The short stature homeobox 2 (Shox2)- bone morphogenetic protein (BMP) pathway regulates dorsal mesenchymal protrusion development and its temporary function as a pacemaker during cardiogenesis. J. Biol. Chem. 290, 2007–23 (2015).
2. Briggs, L. E., Kakarla, J. & Wessels, A. The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation. 84, 117–30 (2012).
3. Liang, X. et al. HCN4 dynamically marks the first heart field and conduction system precursors. Circ. Res. 113, 399–407 (2013).
4. Kelder, T. P. et al. The sinus venosus myocardium contributes to the atrioventricular canal: potential role during atrioventricular node development? J. Cell. Mol.
Med. 19, 1375–89 (2015).
5. Vicente-Steijn, R. et al. Funny current channel HCN4 delineates the developing cardiac conduction system in chicken heart. Heart Rhythm. 8, 1254–63 (2011).
