# Mechanisms of DMP Development and Atrioventricular Septation

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $485,875

## Abstract

Atrioventricular defects (AVSDs) are complex heart malformations found in 5% of patients with congenital heart
disease (CHD). They are particularly prevalent in patients with genetic disorders such as Down Syndrome, and
CHARGE Syndrome. There are two major types of AVSDs. Partial (or incomplete) AVSDs and complete AVSDs.
The partial AVSDs are characterized by the presence of a primary atrial septal defects (pASDs) and a common
AV valves (cAVVs), while in complete AVSDs, in addition to these two abnormalities, ventricular septal defects
(VSDs) are also found. The nature of an AVSD has a significant implication for postnatal treatment. Patients
born with complete AVSDs will typically have to undergo surgery within the first months of life to prevent the
development of pulmonary hypertension, whereas asymptomatic patients with partial AVSDs, may receive
surgery later in life. Individuals with a surgically repaired AVSD may, at one point, require re-operation to address,
for instance, valve insufficiency or pacemaker implantation, or to deal with other conditions that interfere with
proper heart function as they get older. For many years it was believed that AVSDs were caused by failure of
the endocardially-derived AV cushions to develop properly. This belief led to the introduction and use of the term
“endocardial cushion defect”. Studies conducted in our lab on the role of the Dorsal Mesenchymal Protrusion
(DMP) in heart development have, however, significantly shifted this paradigm. The DMP is a Second Heart
Field (SHF)-derived mesenchymal structure located at the venous pole of the heart. Together with the AV
cushions and the mesenchymal cap on the primary atrial septum, the DMP forms the AV mesenchymal complex.
We have recently begun to explore the role of Sox9 in AVSD pathogenesis. Importantly, we found that deletion
of Sox9 from the SHF and from the endocardial lineage both result in complete AVSD. This result has prompted
us to revisit, the current paradigm for the pathogenesis of AVSDs. In this project we will explore the role of Sox9
in the development of each of the mesenchymal structures that contribute to the AV mesenchymal complex and
test the hypothesis in the pSHF, Sox9 is a common downstream target and regulator for signaling pathways
proven to be critical for development of the DMP. We will also test the hypothesis that chromosome-helicase-
DNA-binding protein 7 (Chd7), the gene frequently found to be mutated in patients with CHARGE syndrome and
expressed in the pSHF, is involved in DMP development and AV septation by controlling pSHF proliferation and
by regulating Sox9 expression and p53 activation.

## Key facts

- **NIH application ID:** 9973618
- **Project number:** 2R01HL122906-04A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Arno Wessels
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,875
- **Award type:** 2
- **Project period:** 2014-09-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973618

## Citation

> US National Institutes of Health, RePORTER application 9973618, Mechanisms of DMP Development and Atrioventricular Septation (2R01HL122906-04A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973618. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*