# The role of the ErbB4 and ErbB3 neuregulin receptors in intestinal epithelial regeneration

> **NIH NIH R01** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2021 · $421,741

## Abstract

PROJECT SUMMARY
The receptor tyrosine kinases ErbB4 and ErbB3 can protect intestinal enterocytes from
apoptosis, but their potential roles in inducing stem cell regeneration after an insult—arguably of
equal importance in the face of challenge—are not known. Here, we aim to define the function
of ErbB3 and ErbB4 in post-injury recovery of intestinal stem cells, and thus in regeneration of
the epithelium. ErbB4 expression is high in regenerating enteroids, and the ErbB4 ligand NRG4
promotes crypt plating efficiency. ErbB4-null enteroid cultures have a compromised intestinal
stem cell niche with loss of the rapidly-cycling stem cell marker Lgr5 and reduced Paneth cell
numbers. Similar to ErbB4, ErbB3 promotes enterocyte survival, but unlike ErbB4 it suppresses
secretory cell differentiation; for example, ErbB3-null enteroids have an expanded Paneth cell
census. Thus, the two neuregulin receptors seem to play complementary but distinct roles in
regulating renewal and development in the crypt. Preliminary data suggest that both of these
receptors are induced during recovery from injury models in vitro and in vivo, and loss of either
perturbs recovery. We will build on our published and preliminary data to test the hypothesis
that signaling through ErbB4 and ErbB3 promotes balanced regeneration of the intestinal
epithelium after injury. We will (1) define the impact of ErbB4 or ErbB3 loss or activation on
intestinal epithelial regeneration after injury, (2) determine the molecular mechanisms linking
ErbB4 and ErbB3 to intestinal stem cell regeneration, especially connections to the fundamental
regulators of stem cell self-renewal, Wnt and Notch. These studies will advance basic
understanding of how intestinal stem cells and the stem cell niche are repaired, as well as
identify novel regulatory mechanisms that could be future therapeutic targets to drive intestinal
regeneration after injury.

## Key facts

- **NIH application ID:** 10163158
- **Project number:** 5R01DK095004-08
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** Mark R Frey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $421,741
- **Award type:** 5
- **Project period:** 2013-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163158

## Citation

> US National Institutes of Health, RePORTER application 10163158, The role of the ErbB4 and ErbB3 neuregulin receptors in intestinal epithelial regeneration (5R01DK095004-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10163158. Licensed CC0.

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