# The Role of ESCRTs in Regulating Nervous System Function

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $329,111

## Abstract

Peripheral neuropathies affect more than 20 million people in the United States. Patients with peripheral
neuropathies suffer from debilitating motor and sensory deficits that can cause severe pain and paralysis.
Many forms of inherited peripheral neuropathies impair Schwann cell function and result in abnormal myelin
production or demyelination, which is thought to be the underlying cause of the motor and sensory deficits.
Schwann cells intimately associate with axons to organize peripheral nerves during development and to
insulate axons with myelin. The NRG1/ERBB signaling pathway allows for Schwann cells and axons to
communicate with each other and provides essential instructions that regulate Schwann cell proliferation,
migration and myelination. Modulation of the NRG1/ERBB signaling pathway can restore function to several
rodent models of Charcot-Marie-Tooth disease (CMT). Therefore, identifying the mechanisms that control
NRG1/ERBB signaling has important implications for the treatment of peripheral neuropathies. Our data from
mice and cell culture experiments indicate that the endosome is a critical regulator of ERBB2/3 function during
myelination. To investigate the endosomal pathways controlling ERBB2/3 signaling, we have developed mouse
models that impair endosomal sorting of internalized cell surface receptors. We have focused on hepatocyte
growth factor regulated tyrosine kinase substrate (HGS), which directs the sorting of internalized receptors
through the endosome. HGS expression is diminished in two different mouse models of CMT, implicating
defective endosomal sorting as a cause for demyelinating neuropathies. Our data now indicate that loss of
HGS in Schwann cells replicates many features of inherited peripheral nerve disorders, including motor and
sensory deficits and dysmyelination of sciatic nerves. Impairing endosomal function by deleting the Hgs gene
specifically in Schwann cells also showed that ERBB2/3 receptor signaling is dependent upon endosomal
sorting to activate its downstream signaling pathways. In addition, we have identified a novel endosomal
protein complex in Schwann cells that occurs during myelination. To test the hypothesis that endosomal sorting
regulates ERBB2/3 function during myelination, Aim 1 will determine the role of endosomal sorting in Schwann
cells for the development and function of peripheral nerves, and Aim 2 will determine how endocytic trafficking
controls the sorting and signaling of the ERBB2/3 receptors in Schwann cells. To investigate the mechanism
regulating ERBB2/3 function in Schwann cells, Aim 3 will determine which HGS interacting protein complexes
are required for ERBB2/3 sorting and signaling in Schwann cells. The completion of this proposal is expected
to provide novel insights on the endosomal biology of Schwann cells and further our understanding of how
endosomal sorting controls ERBB receptor signaling during myelination. Our long-range goals are to determine
the regulatory pat...

## Key facts

- **NIH application ID:** 10318602
- **Project number:** 5R01NS110744-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Scott Michael Wilson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $329,111
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318602

## Citation

> US National Institutes of Health, RePORTER application 10318602, The Role of ESCRTs in Regulating Nervous System Function (5R01NS110744-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10318602. Licensed CC0.

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