# Investigating the role for Utrophin in age-related decline of the Merkel lineage

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $327,892

## Abstract

Our sense of touch enables numerous behaviors fundamental to human existence, allowing us to eat,
communicate and survive. Deficits in tactile responsiveness are thought to contribute to the decline of postural
stability and hand grip, and the resulting increase in falling frequency, which is a major factor determining
quality of life and the ability to live independently for the elderly. In mammals, different tactile qualities
(curvature, texture and vibration) are encoded by touch receptors residing in the skin with distinct physiological
properties and morphological end-organs; however, the cellular and molecular mechanisms underlying this
diversity are largely unknown. Furthermore, the regulation of skin stem cells that are responsible for
maintaining the turnover of cellular mechanoreceptors that perceive gentle touch, such as Merkel cells, is
unknown. Our laboratory previously characterized a population of epithelial stem cells that reside in epidermal
touch domes in the skin, termed touch dome stem cells (TDSCs), that are responsible for maintaining the
Merkel lineage during homeostasis. The long-term goal of this proposal is to define the cellular and molecular
basis for TDSC maintenance of the Merkel lineage. Our preliminary data chronicles a dramatic age-related
decline in Merkel cell numbers in human (40 – 90 years of age) and murine (2 – 32 months of age) skin.
However, TDSC numbers remain unchanged. We confirmed that age-related loss of Merkel cells is not due to
precocious exit of mature Merkel cells or defects in sensory afferent innervation but is due to diminished TDSC
progenitor capacity to replenish the Merkel lineage. Leveraging this age-related deficit in TDSC progenitor
capacity, we performed proteomics and mRNA profiling of TDSCs from young versus aged mouse skin and
identified the focal adhesion-associated protein Utrophin (Utrn) to be dramatically downregulated in aged
TDSCs. Utrn null (Utrn-/-) mice at postnatal day 20 displayed equal numbers of Merkel cells compared to Wt
mice, excluding a role for Utrn in Merkel cell development. However, Merkel cell numbers were reduced by
50% in 2-month-old Utrn-/- mice providing genetic evidence for a functional role for Utrn in age-related
maintenance of the Merkel lineage by TDSCs. We identified the Nrg1-Erbb2 signaling axis as a regulator of
Utrn expression in mouse and human epithelial keratinocytes in vitro and TDSCs in vivo. These preliminary
findings support our central hypothesis: Nrg1-Erbb2 regulation of Utrn expression is required for TDSC
maintenance of Merkel cell homeostasis. To test our hypothesis, we will employ mouse models to genetically
disrupt or rescue Utrn expression and assess its impact on Merkel cell homeostasis. Using in vivo lineage
tracing tools and a Nrg1 conditional allele we will investigate the cellular mechanisms underlying TDSC
maintenance of the Merkel lineage and upstream regulation of Nrg1 expression in the TD niche. Finally, we will
interrogate t...

## Key facts

- **NIH application ID:** 10848482
- **Project number:** 5R01AG073874-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** David Michael Owens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $327,892
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848482

## Citation

> US National Institutes of Health, RePORTER application 10848482, Investigating the role for Utrophin in age-related decline of the Merkel lineage (5R01AG073874-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10848482. Licensed CC0.

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