# Prox1 and COUP-TFII interactions regulate lymphatic endothelial cell differentiation

> **NIH NIH F30** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $40,809

## Abstract

PROJECT ABSTRACT
The lymphatic system is a complex vascular and tissue network that transports the lymph fluid containing
proteins, macromolecules, and extravasated cells from peripheral tissues back to the circulation. The flow of
lymph into lymphatic vessels is largely driven by local changes in interstitial pressure, which signals to lymphatic
endothelial cells (LECs) through anchoring filaments in the surrounding extra cellular matrix. In response to
increased interstitial pressure, anchoring filaments pull LECs to widen the overlapping cell-cell junctions and
allow the flow of lymph into lymphatic vessels. Perturbations in development can lead to congenital lymphatic
malformations and malignancies, while disruptions in post-natal lymphatic function can lead to pathologic
lymphatic fluid accumulation and chronic immune and digestive problems. Despite the essential role of LECs in
lymphatic system development and tissue fluid homeostasis, the signals that specify and maintain LEC identify
are not well described. Previous studies have shown that LECs differentiate from venous endothelial cells and
that homeodomain transcription factor Prox1 serves as a master regulator of this lineage conversion process.
During embryogenesis, a subset of venous endothelial cells of the cardinal vein express Prox1 and migrate out
to form rudimentary lymphatic vessels. It is known that these Prox1-positive cells downregulate the expression
of genes associated with venous endothelial identify and upregulate gene expression signatures consistent with
LECs. However, the exact mechanisms underlying Prox1 mediated LEC differentiation are not known. We
previously showed that Prox1 physically interacts with venous endothelial cell fate regulator, COUP-TFII. This
preliminary work suggests that in addition to driving venous endothelial cell differentiation, COUP-TFII, also
works in concert with Prox1 to establish and maintain the LEC lineage, which is the basis for the hypothesis of
the proposed study. The concept that the key molecular regulator of venous endothelial cell identity plays an
essential role in lymphatic development is of great interest and highlights the close histogenetic relationship
between the two vascular systems. By dissecting the molecular interactions between Prox1 and COUP-TFII
during LEC development, this proposal aims to elucidate the gene regulatory networks that orchestrate
endothelial cell differentiation and advance our understanding of arteriovenous-lymphatic vascular development
and disease.

## Key facts

- **NIH application ID:** 10268188
- **Project number:** 5F30HL154324-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Omar Toubat
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,809
- **Award type:** 5
- **Project period:** 2020-08-16 → 2024-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10268188

## Citation

> US National Institutes of Health, RePORTER application 10268188, Prox1 and COUP-TFII interactions regulate lymphatic endothelial cell differentiation (5F30HL154324-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10268188. Licensed CC0.

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