# Neurotrophic factor trafficking and signaling in development and disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $400,287

## Abstract

A fundamental question in neuronal cell biology is how membrane proteins are
transported long-distance to axons after biosynthesis in cell bodies. Axon targeting of
membrane proteins is critical for the formation and maintenance of neuronal connections
and for a functional nervous system. Yet, how most membrane proteins are delivered to
axons remains undefined.
 A long-held view in neurobiology is that signaling receptors are constitutively
delivered to axons via secretory trafficking. In contrast, we found that TrkA neurotrophin
receptors that are essential regulators of neuron survival, axon growth, and inflammatory
pain are actively recruited to axons via transcytosis, an endocytosis-based mechanism
where receptors embedded in soma surfaces are internalized and anterogradely
transported to axons. Strikingly, anterograde TrkA transcytosis is triggered by the ligand,
Nerve Growth Factor (NGF), acting on axon terminals, suggesting a positive feedback
mechanism that serves to dynamically scale up receptor availability in axons during times
of need. Furthermore, we identified that TrkA transcytosis is primed by the activity of
PTP1B, an ER-resident protein tyrosine phosphatase, in cell bodies. The overall goal of
this application is to elucidate the signaling and trafficking mechanisms underlying a
poorly characterized mode of ligand-triggered targeting of receptors to axons. In Aim 1,
we will define NGF-mediated mechanisms that initiate transcytosis in cell bodies,
elucidate the trafficking itinerary and transport kinetics of receptor transcytosis, and
investigate TrkA transcytosis in vivo. In Aim 2, we will test the hypothesis that ER-
anchored PTP1B phosphatase promotes a gain of TrkA biological function by controlling
the long-distance transcytosis of receptors. We will employ live imaging, biochemical, and
functional analyses in compartmentalized neuron cultures in combination with in vivo
analyses of genetically modified mice to accomplish these goals. These studies will
address a fundamental, yet poorly studied, cell biological question of how signaling
receptors are directed to axons, and will provide insight into specialized mechanisms that
enhance neuronal responsiveness to spatially acting extrinsic cues.

## Key facts

- **NIH application ID:** 9897598
- **Project number:** 5R01NS107342-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Rejji Kuruvilla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,287
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897598

## Citation

> US National Institutes of Health, RePORTER application 9897598, Neurotrophic factor trafficking and signaling in development and disease (5R01NS107342-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897598. Licensed CC0.

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