# Dissecting the Molecular Role of TBX1 in the Context of Human Pharyngeal Endoderm Development

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $393,500

## Abstract

PROJECT SUMMARY
22q11.2 Deletion Syndrome (22q11.2DS), the most common of the microdeletion syndromes, is caused by
hemizygous loss of 0.7-3 Mb of DNA on chromosome 22 and results in a constellation of clinical phenotypes.
The core phenotype originates from disrupted development of the pharyngeal apparatus. Particularly affected
are the second heart field-dependent heart structures, great vessels, parathyroids, thymus, and lower
craniofacial and face muscles. Although approximately 50 genes may be deleted, it is the haploinsufficiency of
the transcription factor TBX1 that recapitulates most of the critical phenotype associated with 22q11.2DS.
Genetic and developmental mouse studies have established that TBX1 is critical for typical development of the
pharyngeal endoderm, a transient anatomical structure necessary for development of the thymus, parathyroids,
and 4th pharyngeal arch arteries. Despite this central role, very little is known regarding the molecular
mechanisms by which TBX1 functions in the pharyngeal endoderm. While a handful of studies have attempted
to study the role of TBX1 in human cells, the cell types they have been conducted in are not representative of
the appropriate developmental stage where and when TBX1 plays its critical role. To date, an effort to integrate
all the critical genes into a pharyngeal endoderm or 4th pharyngeal arch arteries network has not been attempted,
particularly in human cells.
This R01 leverages recent development of an in vitro model which faithfully mimics the formation and progression
of human pharyngeal endoderm, thereby providing an unprecedented opportunity to tease out the functions of
TBX1 in its physiological context. Specifically, this model will be used to identify the transcriptional targets and
partners of TBX1 (Aim1), investigate the role of TBX1 as epigenetic regulator of the human pharyngeal endoderm
(Aim2), and mechanistically investigate newly discovered putative regulatory regions of the TBX1 locus (Aim3).
The overarching hypothesis is that TBX1 is at the center of a Gene Regulatory Network critical for both the
formation and maturation of the pharyngeal endoderm and the morpho-patterning of the surrounding mesoderm
and neural crest cells.
The proposed work is expected to identify the molecular mechanism at the basis of TBX1 haploinsufficiency and
identify pathways which could be rescued through pharmacological intervention. Dissection of the epigenetic
and molecular machinery responsible for pharyngeal endoderm formation will be instrumental in informing the
generation of cell therapies for 22q11.2DS.

## Key facts

- **NIH application ID:** 10442889
- **Project number:** 1R01HL157139-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Vittorio Sebastiano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,500
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442889

## Citation

> US National Institutes of Health, RePORTER application 10442889, Dissecting the Molecular Role of TBX1 in the Context of Human Pharyngeal Endoderm Development (1R01HL157139-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10442889. Licensed CC0.

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