# Intersection of signaling pathways and transcription factors regulating islet development

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $601,286

## Abstract

Pancreas agenesis (PA) is a developmental disorder characterized by either a reduction or complete lack of
pancreatic mass. Notably, heterozygous loss of GATA6 accounts for >60% of all human pancreas agenesis
cases; however, the pancreatic phenotype within each individual can be incompletely penetrant, ranging from
severe neonatal diabetes to mild adult onset diabetes due to beta cell dysfunction. These findings suggest that
additional genetic modifiers may contribute to the pathogenesis caused by the reduction in GATA6 expression.
During the previous funding period, the collaboration between the Gadue and Sussel labs leveraged the
strengths of human induced pluripotent stem cell (hiPSC)-based pancreas differentiation and in vivo murine
models of development to discover robust synergy between GATA6 and retinoic acid (RA) signaling in regulating
several stages of pancreas development. Our findings suggest two novel concepts: (1) an unappreciated role
for RA signaling during endocrine progenitor specification and (2) synergy between RA and specifically GATA6
(but not GATA4) is required to specify beta cells in both mice and humans. The primary goals of this renewal
application are to use these complementary genetic model systems to better define this synergy and elucidate
the mechanisms by which the intersection of RA signaling and GATA6 regulate pancreas development.
Furthermore, we will explore how human mutations in GATA6 disrupt this interaction to influence disease
severity. Our published studies combined with new preliminary data in both the mice and human models has led
us to hypothesize that this conserved synergy between RA signaling and GATA6 gene regulation is
essential for pancreas development and the combined disruption of these pathways contributes to
pancreas and islet cell development. We will test this hypothesis with the following specific aims: 1) Establish
the synergistic roles of RA/GATA6 during pancreatic endocrine and β cell development and identify the specific
stages of the hiPSC-derived pancreas differentiation protocol that require a combination of RA signaling and
GATA6 function for optimal beta cell development; 2) Determine the precise molecular mechanism(s) underlying
the intersection of RARa and GATA6 in the regulation gene expression pathways that promote pancreatic islet
differentiation; and 3) Define how patient specific GATA6 disease mutations affect RA/GATA6 synergy and
downstream pathways during pancreas development. The experiments proposed in this application will provide
substantial novel insight into the conserved regulatory pathways that are required for appropriate pancreas
development and islet cell differentiation and will further inform how mutations in GATA6 cause a wide range of
pancreatic phenotypes in humans.

## Key facts

- **NIH application ID:** 10754941
- **Project number:** 5R01DK118155-06
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** PAUL J GADUE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $601,286
- **Award type:** 5
- **Project period:** 2018-07-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754941

## Citation

> US National Institutes of Health, RePORTER application 10754941, Intersection of signaling pathways and transcription factors regulating islet development (5R01DK118155-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10754941. Licensed CC0.

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