27 February

Signaling proteins in pacemaker cells regulate cardiac rhythm

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A signaling process with which cells pass on signals during cardiac development, called Wnt/ß-catenin-signaling, influences the control of the autonomic nervous system on heart rate in zebrafish. That is the conclusion of Silja Burkhard, one of the Hubrecht researchers of the Bakkers group. For this research, she used tomo-seq, a technique developed at the Hubrecht Institute. The results have recently been published in eLife.

The heart is responsible for continuously pumping blood through the body during our entire lives. The contraction of the heart is initiated by the pacemaker cells, specialized heart cells, located in the sinus node, regulating heart rhythm and heart rate. They are also able to elevate the heart rate during sports or lower it when the body is at rest. Pacemaker cells can be found in zebrafish too. This model system is suitable for research into the developmental biology of the heart, because the genome is fully sequenced, the embryonal development is fast and the fish are transparent until gestation. During her PhD, Silja Burkhard already conducted research on cardiac development in zebrafish.

To find out more about the pacemaker cells in the zebrafish, Burkhard used tomo-seq, a technique that was recently developed in the Hubrecht Institute. Using this technique, she cut the heart of a two-day old zebrafish in very thin slices (see figure) and analyzed the gene expression in each of them. This way, she was able to investigate the expression of genes at any specific place in the heart while keeping information of the spatial structure.

Een zebravissenhart van drie dagen oud. Grijs: hartspiercellen. Groen: pacemakercellen. Rood: cellen met actieve Wnt-signalering.

Signaling and regulating
From tomo-seq, Burkhard concluded that pacemaker cells express genes involved in the Wnt/ß-catenin-signaling – a process with which cells pass on signals during cardiac development. Until now, the role of this signaling pathway in pacemaker cell development was elusive. Burkhard confirmed the significance of Wnt and ß-catenin in this process by inhibiting these two signaling proteins and observing an elevated heart rate. Her conclusion is that Wnt/ß-catenin-signaling regulates the response of pacemaker cells to stimuli of the autonomic nervous system – the part of the nervous system that also brings the human body in a state of rest.

Biological pacemaker
Fundamental research to the genetic expression in the zebrafish heart may be far from treating patients with cardiac abnormalities – it is important to gain knowledge on the molecular mechanisms behind cardiac conduction. This research might help us understand the process and take us one step closer to the biological pacemaker.


Jeroen Bakkers is group leader at the Hubrecht Institute (KNAW) and Professor of Molecular Cardiogenetics at the University Medical Center Utrecht.

Spatially resolved RNA-sequencing of the embryonic heart identifies a role for Wnt/ß-catenin signaling in autonomic control of heart rate.
Silja Burkhard, Jeroen Bakkers.
eLife 2018;7:e31515.