# Morphogenesis and function of somatosensory axon ensheathment by epidermal cells

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $421,507

## Abstract

PROJECT SUMMARY
Selective interactions between neurons and non-neuronal cells are crucial for the development and function of
neural circuits. Pain-sensing somatosensory neurons project peripheral axons to the skin, where they branch
extensively amongst epithelial epidermal cells. Although these sensory terminals are called “free endings”,
recent studies have revealed that they are often wrapped by epidermal cells, which enclose them into
ensheathment channels reminiscent of those formed by non-myelinating Remak Schwann cells. Although
underappreciated, epidermal ensheathment channels have been observed in worms, flies, fish, and mammals,
indicating that ensheathment is a conserved feature of epidermal sensory endings, and thus likely plays critical
roles in the development and function of nociceptive axons. Little is known about the morphogenetic process of
axon ensheathment by epidermal cells, and nothing is known about how these structures contribute to sensory
function or disease in vertebrate animals.
This proposal investigates the morphogenetic mechanisms that create epidermal ensheathment channels and
how they contribute to sensory function in zebrafish larvae. Their external development and the availability of
unique transgenic tools make zebrafish an ideal model for studying this dynamic morphogenetic process.
Preliminary work using live fluorescent reporters for subcellular structures in zebrafish skin cells identified a
sequence of events leading up to ensheathment and suggested a step-wise morphogenetic process. First,
axons growing into this epidermis induce the formation of specialized lipid microdomains at skin cell-axon
contact sites. Second, F-actin is recruited to these microdomains, likely promoting membrane invagination to
initiate the ensheathment process. Finally, adherens junctions and desmosomes form at “necks” of
ensheathment channels to tightly seal the channels. The first two aims of this proposal use innovative
microscopy approaches for high spatial and temporal resolution live imaging, cell-specific molecular
manipulations, and CRISPR/Cas9-mediated mutagenesis to determine how axons and skin cells establish
selective interactions and execute the ensheathment process. These studies will illuminate morphogenetic
mechanisms relevant not just to axon ensheathment by epidermal and glial cells, but also to basic cellular
processes, like the formation of membrane signaling domains and junction assembly. The third aim combines
imaging and behavioral assays to reveal how axon ensheathment impacts neuronal structure and function.
These studies have the potential to uncover a critical feature of the touch-sensing apparatus and suggest how
ensheathment contributes to disease conditions affecting pain and touch sensation.

## Key facts

- **NIH application ID:** 10071530
- **Project number:** 2R01AR064582-11
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Alvaro Sagasti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,507
- **Award type:** 2
- **Project period:** 2014-05-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071530

## Citation

> US National Institutes of Health, RePORTER application 10071530, Morphogenesis and function of somatosensory axon ensheathment by epidermal cells (2R01AR064582-11). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071530. Licensed CC0.

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