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<p>Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect, but mechanisms for patterning the IVS are largely unknown. Here we show that a <i>Tbx5</i><sup><i>+</i></sup><i>/Mef2cAHF</i><sup>+</sup> progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first and second heart field interface. Ablation of <i>Tbx5</i><sup><i>+</i></sup><i>/Mef2cAHF</i><sup>+</sup> progenitors causes IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the congenital heart defect transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects and patterning defects, including misexpression of <i>Slit2</i> and <i>Ntn1</i>, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in <i>Tbx5</i> mutant embryos. Loss of <i>Slit2</i> or <i>Ntn1</i> causes ventricular septation defects and perturbed septal lineage distributions. Thus, we identify <i>Tbx5</i> as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects.</p>

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A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Irfan S. Kathiriya,
  • Martin H. Dominguez,
  • Kavitha S. Rao,
  • Jonathon M. Muncie-Vasic,
  • W. Patrick Devine,
  • Kevin M. Hu,
  • Swetansu K. Hota,
  • Bayardo I. Garay,
  • Diego Quintero,
  • Piyush Goyal,
  • Megan N. Matthews,
  • Reuben Thomas,
  • Tatyana Sukonnik,
  • Dario Miguel-Perez,
  • Sarah Winchester,
  • Emily F. Brower,
  • André Forjaz,
  • Pei-Hsun Wu,
  • Denis Wirtz,
  • Ashley L. Kiemen,
  • Benoit G. Bruneau

摘要

Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect, but mechanisms for patterning the IVS are largely unknown. Here we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors causes IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the congenital heart defect transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes ventricular septation defects and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects.