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

## TL;DR

This study identifies a specific heart progenitor lineage that forms a boundary in the heart's septum, and disruptions in this lineage lead to congenital heart defects in mice.

## Contribution

The paper discovers a Tbx5+/Mef2cAHF+ progenitor lineage that forms a critical boundary for cardiac septation and contributes to congenital heart defects when disrupted.

## Key findings

- Ablation of Tbx5+/Mef2cAHF+ progenitors causes IVS disorganization and right ventricular hypoplasia.
- Reduced TBX5 dosage disrupts boundary integrity and leads to septation and patterning defects.
- Reducing NTN1 dosage partially rescues cardiac defects in Tbx5 mutant embryos.

## Abstract

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.

Kathiriya et al. identify a cardiac progenitor lineage with expression of Tbx5 and anterior heart field-specific expression of Mef2c that bisects the intraventricular septum during development and show that alterations in this lineage lead to congenital heart defects in mice.