# Regulation of Fibronectin expression in the neural crest during vascular morphogenesis

> **NIH NIH F31** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $62,826

## Abstract

7. PROJECT ABSTRACT
Congenital heart disease (CHD) is the most common human birth defect, with approximately 40,000 newborns
affected annually in the United States. CHD is characterized by any defect in the formation of the heart and is
often most severe when involving defects of the aortic arch artery (AAA) vasculature. The AAAs route
oxygenated blood from the heart throughout the body and are formed from the remodeling of three pairs of
pharyngeal arch arteries (PAAs), namely the 3rd, 4th and 6th. PAA-to-AAA remodeling depends upon a population
of stem-like cells known as cardiac neural crest cells (cNCCs), and their differentiation to vascular smooth muscle
cells (vSMCs) in the PAAs. Defective cNCC-to-vSMC differentiation results in AAA abnormalities including
interrupted aortic arch, a severe defect of the 4th PAA which necessitates surgery upon birth. The extreme nature
of arch artery defects resulting from defective cNCC-to-vSMC differentiation presents the need to investigate
normal processes of cNCC-to-vSMC differentiation with a particular focus on the sensitivity of the 4th PAA to
defects. Our lab previously found that the extracellular matrix protein, Fibronectin (Fn1), is essential for the
process of cNCC-to-vSMC differentiation. Fn1 is expressed in cNCCs along a spatiotemporal gradient in murine
pharyngeal arches. At E9.5, its expression is detected in migrating cNCCs; but by E10.5, when cNCCs are filling
the PAAs, its expression is attenuated. By E11.5, just prior to cNCC-to-vSMC differentiation, its expression is
restored in such a manner that cNCCs closest to the PAA lumen exhibit the highest expression while those
farther away exhibit less, phenocopying the pattern of cNCC-to-vSMC differentiation. Ablation of Fn1, specifically
in cNCCs, results in attenuated vSMC differentiation and defective PAA-to-AAA remodeling. This phenotype is
not rescued by exogenous Fn1 or the presence of other matrix proteins, indicating the cell-autonomous function
of Fn1 in cNCCs. As critical as Fn1 is in cNCC-to-vSMC differentiation and downstream PAA-to-AAA remodeling,
how its expression is regulated in cNCCs is unknown. We hypothesize that the induction of Fn1 within cNCCs
is initiated by blood-flow induced TGFβ signaling in cNCCs or the endothelium. We propose to investigate
the role of the TGFβ superfamily (via Smad4) in regulating Fn1 in cNCCs for various reasons: (1) The role that
the TGFβ family plays in regulating Fn1 during embryogenesis is not well understood (2) TGFβ is a
mechanoresponsive pathway which may regulate the spatiotemporal gradient of Fn1 in response to blood flow
(3) there is controversy over the role of TGFβ in cNCC development and (4) there are improved genetic tools
which will allow us to investigate TGFβ signaling in our system. Our preliminary data suggests that Smad4 is
important for cNCC-specific Fn1 production in the pharyngeal arches, yet we do not know the cell type in which
Smad4 must function for this response. We p...

## Key facts

- **NIH application ID:** 10110111
- **Project number:** 3F31HL151046-01S1
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Brianna Alexander
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $62,826
- **Award type:** 3
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110111

## Citation

> US National Institutes of Health, RePORTER application 10110111, Regulation of Fibronectin expression in the neural crest during vascular morphogenesis (3F31HL151046-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10110111. Licensed CC0.

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