# Transcriptional clues to esophageal atresia pathogenesis

> **NIH NIH R03** · UNIVERSITY OF PENNSYLVANIA · 2020 · $81,000

## Abstract

Project Summary
Esophageal atresia (EA) is the most common congenital disorder of the esophagus with a worldwide incidence
of about 1 in 3,500 live births. EA can occur as an isolated finding, or in combination with either syndromic or
non-syndromic developmental anomalies. Left untreated, EA is a fatal disorder because the atretic segment
obstructs the esophagus. Fortunately, it can be cured surgically in nearly all infants, however the majority suffer
from severe gastroesophageal reflux and dysphagia as a result of impaired esophageal motility. Although the
cause of EA is not known, a genetic component is predicted based on its occurrence in complex developmen-
tal syndromes and its higher incidence in monozygotic vs. dizygotic twins. No single gene mutations have been
conclusively shown to cause EA. We have developed the first animal model of isolated EA by engineering a
mutation in the smooth muscle myosin heavy chain gene (Myh11) that we have previously shown alters myosin
regulation. In zebrafish, the identical mutation causes invasive expansion of the intestine. In mice the predomi-
nant phenotype is EA, although invasive-like intestinal lesions are detected. The mutation disrupts smooth
muscle contractility as a result of altered myosin regulation. This suggests that genetic variants in MYH11 and
other smooth muscle regulatory genes could cause both EA and its associated esophageal motility disorders.
Preliminary transcriptional profiling studies of esophagi from Myh11 mutants before the EA phenotype is de-
tected showed altered regulation of genes involved in nervous system and striated muscle development. This
suggest that defects in esophageal neuromuscular function may be an intrinsic defect associated with EA that
arises independently of atresia. Supporting this, immunostainings show altered esophageal nerve fiber density,
reduced number and size of esophageal ganglia and altered striated muscle development in mutant esophagi
The goal of this proposal is to expand these findings by examining these and other gene expression changes
in older Myh11 mutants, by quantifying changes in neuronal density and neuronal subtypes, and by conducting
in vitro functional analyses in primary cultures of esophageal neurons.

## Key facts

- **NIH application ID:** 9978320
- **Project number:** 1R03HD099667-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MICHAEL A PACK
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $81,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978320

## Citation

> US National Institutes of Health, RePORTER application 9978320, Transcriptional clues to esophageal atresia pathogenesis (1R03HD099667-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978320. Licensed CC0.

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