# Cell fate choices by Tbx1 in forming the mammalian heart

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $605,558

## Abstract

TBX1 encodes a T-box transcription factor required for cardiac development. This gene maps to
the chromosome 22q11.2 region that is deleted in patients with DiGeorge syndrome/velo-cardio-
facial syndrome or 22q11.2 deletion syndrome (22q11.2DS). Approximately 60% of 22q11.2DS
patients have congenital heart disease that mostly affects the cardiac outflow tract. A subset of
individuals with a mutation of the TBX1 gene but not a deletion has been identified and they
partially phenocopy patients with 22q11.2DS. Inactivation of one allele of Tbx1 in mice results in
mild defects, but inactivation of both alleles results in neonatal lethality with a persistent truncus
arteriosus, in which the aorta and pulmonary trunk fail to separate. This defect also occurs in 5-
10% of 22q11.2DS patients with congenital heart disease. To understand the function of Tbx1 in
mammals, we performed single cell RNA-sequencing (scRNA-seq) of cardiopharyngeal
mesoderm progenitor cells within the pharyngeal apparatus. We discovered a multilineage
progenitor (MLP) population that expresses genes important for forming the cardiac outflow tract
as well as branchiomeric muscles of the face and neck. The MLP population expands at the
expense of more differentiated populations when Tbx1 is inactivated in the cardiopharyngeal
mesoderm. Our main hypothesis is that Tbx1 is required in the MLP population for progression
towards more differentiated states needed for cardiac development. We propose three specific
aims to test this hypothesis. In the first aim, we will perform additional scRNA-seq experiments
and analyze the complete dataset to understand how the progression of MLP cells are altered in
Tbx1 conditional and global mutant mouse embryos. In Aim 2, we will determine where the MLP
cells are localized in the embryo. Preliminary data suggests that these cells are localized to the
nascent mesenchyme of the elongating pharyngeal apparatus. We will also inactivate Tbx1
specifically within the MLP cells to determine its particular functions. In Aim 3, we will turn to
functional genomic studies and will identify open and accessible chromatin for which harbors
TBX1 protein binding sites using ATAC-seq and ChIP-seq from embryo tissue. Preliminary data
suggests that we are able to identify direct transcriptional target genes. By these three aims, we
will understand the molecular functions of TBX1 in the progression of progenitor cells to more
differentiated states to build the cardiac outflow tract.

## Key facts

- **NIH application ID:** 10242828
- **Project number:** 5R01HL153920-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** BERNICE E MORROW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $605,558
- **Award type:** 5
- **Project period:** 2020-08-20 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242828

## Citation

> US National Institutes of Health, RePORTER application 10242828, Cell fate choices by Tbx1 in forming the mammalian heart (5R01HL153920-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242828. Licensed CC0.

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