Abstract
The rhythmic contraction of the heart is initiated and controlled by an intrinsic pacemaker system. Cardiac contractions commence at very early embryonic stages and coordination remains crucial for survival. The underlying molecular mechanisms of pacemaker cell development and function are still not fully understood. Heart form and function show high evolutionary conservation. Even in simple contractile cardiac tubes in primitive invertebrates, cardiac function is controlled by intrinsic, autonomous pacemaker cells. Understanding the evolutionary origin and development of cardiac pacemaker cells will help us outline the important pathways and factors involved. Key patterning factors, such as the homeodomain transcription factors Nkx2.5 and Shox2, and the LIM-homeodomain transcription factor Islet-1, components of the T-box (Tbx), and bone morphogenic protein (Bmp) families are well conserved. Here we compare the dominant pacemaking systems in various organisms with respect to the underlying molecular regulation. Comparative analysis of the pathways involved in patterning the pacemaker domain in an evolutionary context might help us outline a common fundamental pacemaker cell gene programme. Special focus is given to pacemaker development in zebrafish, an extensively used model for vertebrate development. Finally, we conclude with a summary of highly conserved key factors in pacemaker cell development and function.
Highlights
The heart is an evolutionary success story
The network of transcription factors regulating mammalian embryonic heart development shows a high degree of evolutionary conservation
Tahbeilyitayretolorchatyetdhimn ically the sinoatrial node (SAN) in mammals and the corresponding structures in other vertebrates and depolarise and initiate an action potential is responsible for the basal heart rate
Summary
The heart is an evolutionary success story. During the course of evolution, novel structures and functions have been added to the primitive ancient pump. Tahbeilyitayretolorchatyetdhimn ically the sinoatrial node (SAN) in mammals and the corresponding structures in other vertebrates and depolarise and initiate an action potential is responsible for the basal heart rate. Pacemaker cells are directly coupled to each other as well as to the adjacent working myocardial cells by gap junctions These allow the exchange of ions from cell to cell, propagating the action potential from the pacemaker cells through the entire myocardium. Pacemaker cells express slow-conducting connexins, Cx45 and Cx32 [25,26] This ensures the unidirectional propagation of the electrical signal from the pacemaker cells to the working myocardial cells. Did the distinct pacemaker evolve out of necessity to accommodate the increasing morphological complexity of the heart in vertebrates to ensure a controlled contraction pattern? Did the distinct pacemaker evolve out of necessity to accommodate the increasing morphological complexity of the heart in vertebrates to ensure a controlled contraction pattern? Did it evolve to ensure coordinated, unidirectional blood flow in a separated systemic-pulmonary circuit? Was it crucial as a mediator to allow heart regulation by the nervous system?
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