# Regulation of the Desmosomal Cadherin, Desmoglein-1, dynamics during epidermal differentiation

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2020 · $40,733

## Abstract

Project Summary
The epidermis is a multilayered epithelial tissue with a critical barrier function that regenerates through the
proliferation of basal cells which exit the cell cycle and transit into suprabasal layers where they undergo
differentiation and formation of the barrier. Regulating the differentiation and morphogenesis of the epidermis is
a desmosomal cadherin called desmoglein-1 (Dsg1). Our lab previously showed that the proper positioning of
newly expressed Dsg1 on the plasma membrane recruits the actin nucleator complex Arp2/3 to junctions where
it stimulates cortical actin remodeling, tension redistribution, and basal cell delamination. To identify trafficking
machinery that regulates Dsg1 delivery we conducted a Dsg1 and E-cadherin protein interaction screen. We
identified VPS35, an essential component of an endosomal trafficking complex called the retromer, as a putative
Dsg1-interacting partner that was not present in the E-cadherin screen. To test if endosomal trafficking is
necessary for the delivery of Dsg1 to the plasma membrane, we inhibited endosomal trafficking with Primaquine,
which resulted in a decrease of Dsg1, but not E-cadherin, localization on the plasma membrane and
accumulation of Dsg1 in VPS35 positive endosomes. Depletion of VPS35 in primary human keratinocyte culture
resulted in decreased Dsg1 plasma membrane localization and protein expression due to lysosomal degradation.
Therefore, it is hypothesized that the retromer complex is necessary for the endosomal trafficking of Dsg1 to the
plasma membrane (AIM1). I will investigate if the retromer regulates endosome to plasma membrane trafficking
of Dsg1 by using biochemical and immunofluorescence recycling assays. Moreover, I will test if pharmacological
enhancement of the retromer function with R55 compound is sufficient to enrich wild-type and a disease-
associated trafficking deficient Dsg1 mutant on the plasma membrane. Delivery of Dsg1 to the plasma
membrane promotes an Arp2/3-dependent increase in the concentration of cortical actin filaments. The role of
Arp2/3-mediated actin remodeling during keratinocyte differentiation is unclear. Preliminary evidence suggests
the pharmacological disruption of actin and Arp2/3 results in the internalization of Dsg1 and impairment in
stratification, respectively. Considering initial recruitment of Dsg1 on the plasma membrane in committed basal
cells promotes the enrichment of cortical actin, these data suggest a feed-forward event where Dsg1 regulation
of actin organization promotes Dsg1 plasma membrane stabilization during epidermal differentiation and
stratification (AIM2). I will explore the role of Arp2/3 and actin in regulating Dsg1 plasma membrane stabilization
and internalization during different stages of keratinocyte differentiation. Additionally, I will investigate Arp2/3’s
role in regulating Dsg1-mediated stratification. These experiments will deepen our understanding of how Dsg1
is properly localized and stab...

## Key facts

- **NIH application ID:** 9991467
- **Project number:** 1F31AR076188-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marihan Hegazy
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,733
- **Award type:** 1
- **Project period:** 2020-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991467

## Citation

> US National Institutes of Health, RePORTER application 9991467, Regulation of the Desmosomal Cadherin, Desmoglein-1, dynamics during epidermal differentiation (1F31AR076188-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9991467. Licensed CC0.

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