Nkx2-5 defines a subpopulation of pacemaker cells and is essential for the physiological function of the sinoatrial node in mice

Hua Li, Dainan Li, Yuzhi Wang, Zhen Huang, Jue Xu, Tianfang Yang, Linyan Wang, Qinghuang Tang, Chen Leng Cai, Hai Huang, Yanding Zhang, Yiping Chen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The sinoatrial node (SAN), the primary cardiac pacemaker, consists of a head domain and a junction/tail domain that exhibit different functional properties. 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 to those manifested by the SAN head and the surrounding atrial cells, suggesting a specific role for the junction cells in impulse generation and in SAN-atrial exit conduction. Singlecell 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.

Original languageEnglish
Article numberdev178145
JournalDevelopment (Cambridge)
Volume146
Issue number14
DOIs
StatePublished - Jul 2019
Externally publishedYes

Keywords

  • Cardiac conduction system
  • Nkx2-5
  • Shox2
  • Sinoatrial node
  • Sinus node dysfunction

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