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Cardiac conduction system malformations in heterotaxy result from dysregulated Pitx2 expression

Kunihiko Joo1,2, Ryohei Matsuoka1,3, Keiko Kitajima1

  • 1Department of Developmental Biology.

JCI Insight
|February 24, 2026
PubMed

Insights

Aberrant left-right (L-R) axis formation disrupts cardiac conduction system (CCS) development. This study reveals Pitx2

Area of Science:

  • Developmental Biology
  • Cardiovascular Science
  • Genetics

Background:

  • The cardiac conduction system (CCS) develops asymmetrically.
  • Heterotaxy syndrome, caused by abnormal left-right (L-R) axis formation, leads to conduction defects and arrhythmias.
  • Mechanisms governing the atrioventricular conduction system (AVCS) in laterality defects are poorly understood.

Purpose of the Study:

  • Investigate the etiology of AVCS malformations in mouse models with laterality defects.
  • Analyze the role of Cryptic, Lefty1, and Pitx2 in regulating AVCS development.
  • Elucidate how L-R axis information influences AVCS integrity.

Main Methods:

  • Analysis of cardiac conduction system development and function in Cryptic and Lefty1 mouse mutants.
  • Single-cell transcriptomic analysis of Pitx2-deficient hearts.
  • Genetic lineage tracing in mouse embryos.

Main Results:

  • Cryptic-/- embryos showed bilateral SA nodes and ectopic AV node with reduced Pitx2.
  • Lefty1-/- embryos exhibited hypoplastic SA node and AV node-bundle dissociation with ectopic Pitx2.
  • Pitx2 deficiency led to expanded AV node and bundle populations, indicating Pitx2's repressive role in AVCS specification.

Conclusions:

  • Pitx2 acts as a key regulator, suppressing AVCS development in specific cardiac regions.
  • Global L-R axis information is locally integrated to shape AVCS disposition and integrity.
  • Provides a mechanistic model for AVCS abnormalities in laterality-associated congenital heart disease.

Keywords:
CardiologyCardiovascular diseaseDevelopmentEmbryonic development

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