Cardiac pacemaker cells of the Sinoatrial Node are essential for producing rhythmic heartbeats. Despite the importance of this specialized cardiac cell type, little is known about their ontogeny or mechanisms of specification and differentiation. Our preliminary data show that although the primary heart tube initially displays rhythmic beating, the cells pacing it do not differentiate into the Sinoatrial Node. Instead, pacemaker precursors arise from the mesoderm posterior to the known cardiogenic field and take over the pacing function during heart-looping. Surprisingly, the pacemaker precursor mesoderm can differentiate in culture without any other surrounding embryonic tissues. They display sustained rhythmic beat rates, and sensitivity to pacemaker cell specific ion channel blockers. Furthermore, they have the ability to pace other cardiomyocyte populations. Our global RNA profiling has identified a unique set of Wnt-related genes expressed in pacemaker precursors. These somewhat surprising findings lead to three central hypotheses: (1) the pacemaker precursors arise from a specific mesoderm population separate from the heart field;(2) pacemaker cell fate is induced prior to heart tube formation;and (3) Wnt-related signaling, which is inhibitory to the heart field, acts as a promoting signal during pacemaker cell specification. We will test these hypotheses experimentally. This proposal will provide the first basis for identifying the embryonic origin of pacemaker precursors (Aim 1), the ability of a specific mesoderm subpopulations to enter the pacemaker cell fate (Aim 2), and novel molecular mechanisms that specify and direct the differentiation this important cell type during a brief temporal window and at a defined site in the embryo (Aim 3).

Public Health Relevance

The cardiac pacemaker is essential for cardiac function and survival. Limited options of effective treatments contribute to the continued prevalence of arrhythmic heart disease. The proposed study will explore the molecular mechanisms that regulate the earliest developmental steps leading to the generation of this essential cardiac tissue and may provide a basis for future therapeutic approaches.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
Zip Code
Hua, Lisa L; Mikawa, Takashi (2018) Chromosome Painting of Mouse Chromosomes. Methods Mol Biol 1752:133-143
Bressan, Michael; Henley, Trevor; Louie, Jonathan D et al. (2018) Dynamic Cellular Integration Drives Functional Assembly of the Heart's Pacemaker Complex. Cell Rep 23:2283-2291
Venters, Sara J; Mikawa, Takashi; Hyer, Jeanette (2015) Early divergence of central and peripheral neural retina precursors during vertebrate eye development. Dev Dyn 244:266-76
Bressan, Michael; Mikawa, Takashi (2015) Avians as a model system of vascular development. Methods Mol Biol 1214:225-42
Bressan, Michael; Yang, PoAn Brian; Louie, Jonathan D et al. (2014) Reciprocal myocardial-endocardial interactions pattern the delay in atrioventricular junction conduction. Development 141:4149-57
Bressan, Michael C; Louie, Jonathan D; Mikawa, Takashi (2014) Hemodynamic forces regulate developmental patterning of atrial conduction. PLoS One 9:e115207
Venters, Sara J; Mikawa, Takashi; Hyer, Jeanette (2013) Central and peripheral retina arise through distinct developmental paths. PLoS One 8:e61422
Czeisler, Catherine; Mikawa, Takashi (2013) Microtubules coordinate VEGFR2 signaling and sorting. PLoS One 8:e75833
Bressan, Michael; Liu, Gary; Mikawa, Takashi (2013) Early mesodermal cues assign avian cardiac pacemaker fate potential in a tertiary heart field. Science 340:744-8
Maya-Ramos, Lisandro; Cleland, James; Bressan, Michael et al. (2013) Induction of the Proepicardium. J Dev Biol 1:82-91