# The role of Ldb1 in regulating pancreatic islet cell delamination and differentiation

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $45,472

## Abstract

PROJECT SUMMARY
Pancreatic islets are comprised of five hormone-secreting cell types and are vital regulators of glucose
homeostasis in mammals. Specifically, glucagon producing α-cells and insulin producing b-cells act
synchronously to tightly regulate blood glucose and allow for normal metabolic function in tissues. During
diabetes, loss of functional b-cell mass leads to severe complications in suffering patients. With diagnoses of
diabetes rising at an alarming rate worldwide, key to future diabetes treatments is a greater
understanding of the transcriptional complexes mediating not only early b-cell, but whole islet
differentiation and formation. The first step of specification of all islet cells is the delamination of endocrine
progenitors (marked by Neurogenin3, Ngn3) out of the ductal epithelium through a process known as epithelial
to mesenchymal transition (EMT), mediated by the Snail2 transcription factor. This step occurs as early as
embryonic day (E)10.5 in mice and is absolutely required for formation of mature islets. Our lab previously
showed that a transcriptional co-regulator, LIM domain binding protein 1 (Ldb1) is required for pancreatic
development at various stages. In a pancreas-wide Ldb1 knockout, we observed disrupted progenitor pools at
E13.5, and a severe loss of Ngn3+ endocrine progenitors at E15.5. Upon birth, these mice lack islet structures,
highlighting the importance of Ldb1 in the development of endocrine cells and formation of islet structures.
Additionally, these neonatal mutant mice exhibited an abnormal clustering of immature endocrine cells along the
ducts. This observation, plus the loss of Ngn3+ cells, suggests that there is a delamination defect during
development. For this training plan, I propose to investigate the role of Ldb1 in pancreatic endocrine
progenitor delamination and the mechanisms by which Ldb1 complexes impart their effects. My
overarching hypothesis is that Ldb1 is required for development of the endocrine progenitor population. In Aim
1, I will determine the contribution of Ldb1 to endocrine progenitor delamination, by assessing canonical EMT
markers throughout development, as well as lineage tracing to determine the fate of endocrine progenitors in the
absence of Ldb1. In Aim 2, I will characterize Ldb1-mediated regulatory mechanisms, with a focus on Ldb1
regulation of Ngn3 and Snail2. I will use Chromatin ImmunoPreciptation (ChIP)-Seq to determine targets directly
bound by Ldb1, and RNA-Seq to gain insight into the genome-wide effects of Ldb1 loss in endocrine progenitors.
A greater understanding of transcriptional control of EMT in the developing pancreas gained from this research
will provide a deeper understanding of how islets arise, benefiting future diabetes therapies, including directed
stem cell differentiation strategies.

## Key facts

- **NIH application ID:** 10307990
- **Project number:** 5F31DK120217-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Eliana Toren
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $45,472
- **Award type:** 5
- **Project period:** 2019-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307990

## Citation

> US National Institutes of Health, RePORTER application 10307990, The role of Ldb1 in regulating pancreatic islet cell delamination and differentiation (5F31DK120217-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10307990. Licensed CC0.

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