Open AccessNkx2-5 defines a subpopulation of pacemaker cells and is essential for the physiological function of the sinoatrial node in mice
Author(s) -
Hua Li,
Dainan Li,
Yuzhi Wang,
Zhen Huang,
Jue Xu,
Tianfang Yang,
Linyan Wang,
Qi Tang,
Chen-Leng Cai,
Hai Huang,
Yanding Zhang,
Yiping Chen
Publication year - 2019
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.178145
Subject(s) - sinoatrial node , biology , gap junction , morphogenesis , microbiology and biotechnology , population , heart development , embryonic stem cell , anatomy , medicine , gene , genetics , endocrinology , intracellular , heart rate , environmental health , blood pressure
The sinoatrial node (SAN), the primary cardiac pacemaker, consists of a head domain and a junction/tail domain that exhibit different functional property. However, the underlying molecular mechanism defining these two pacemaker domains remains elusive. Nkx2-5 is a key transcription factor essential for the formation of the working myocardium, but it was generally thought to be detrimental to SAN development. However, Nkx2-5 is expressed in the developing SAN junction, suggesting a role for Nkx2-5 in SAN junction development and function. In this study, we present unambiguous evidence that SAN junction cells exhibit unique action potential configurations intermediate of those manifested by the SAN head and the surrounding atrial cells, suggesting a specific role for the junction cells in impulse generation and SAN-atrial exit conduction. Single-cell RNA-seq analyses support this concept. Although Nkx2-5 inactivation in the SAN junction did not cause a malformed SAN at birth, the mutant mice manifested sinus node dysfunction. Thus, Nkx2-5 defines a population of pacemaker cells in the transitional zone. Despite Nkx2-5 being dispensable for SAN morphogenesis during embryogenesis, its deletion hampers atrial activation by the pacemaker.