# Rosettes in Adrenal Development, Maintenance and Disease

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $775,328

## Abstract

The adrenal cortex continuously remodels in response to physiological cues, though the precise cellular and
molecular mechanisms remain poorly understood. Our prior studies show that the adrenal cortex undergoes
zonal transdifferentiation during postnatal development in the zona Glomerulosa (zG) gives rise to the zona
Fasciculata (zF). This process involves formation and resolution of multicellular zG-rosettes via the adherens
junction(AJ)-aCatenin complex. How these structures regulate aldosterone production and how dysregulation
leads to disease is not known. Given that primary aldosteronism (PA), the most common form of endocrine
hypertension, involves hyperplasic expansion of zG-rosettes, further study of the factors and signaling pathways
involved in regulating zG development and maintenance is warranted. Utilizing a zG-specific b-catenin gain-of-
function mouse model, we have shown that zG hyperplasia in PA is driven by a block in rosette
resolution/transdifferentiation. In addition, this block involves up regulation of FGFR2 signaling, which is required
for rosette formation during normal development. Further, we have found that rosettes act as a coordinating
center for Ca2+ signaling, via the AJ-aCatenin complex, and subsequent aldosterone production. We also
discovered that WNT2B, recently identified by GWAS analysis as a major risk allele for PA, is a novel regulator
of aldosterone production and zG homeostasis. Based on our recent findings, it is increasing evident that further
study of the role of AJs, rosettes and the signals that control them is necessary. Thus, we propose the following:
 Aim 1. Define how WNT2B mediates zG morphogenesis and function.
 Aim 2. Determine how a-Catenin and AJs mediate zG morphogenesis and function.
 Aim 3. Establish how FGFR2 regulates zG morphogenesis and function.
 These studies seek to understand the regulatory mechanisms that control zG function during postnatal
development and maintenance. The successful completion of these studies will provide critical insights into the
mechanisms that govern zG homeostasis and the initiation and progression of PA, which may lead to new
targeted therapies for this disease.

## Key facts

- **NIH application ID:** 10883000
- **Project number:** 2R01DK123694-06
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** David T Breault
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $775,328
- **Award type:** 2
- **Project period:** 2019-09-19 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883000

## Citation

> US National Institutes of Health, RePORTER application 10883000, Rosettes in Adrenal Development, Maintenance and Disease (2R01DK123694-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10883000. Licensed CC0.

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