# Regulation of axon outgrowth by retrograde Ret signaling

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $365,681

## Abstract

During development or following injury, axon terminals must navigate through a complex environment to form
functional connections. Ret is a neurotrophin receptor which is present at the tips of growing axons. Ret
activation and internalization induces retrograde transport of the activated receptor to the cell body triggering a
transcriptional response, which in turn promotes axon outgrowth. Despite its essential role during nervous
system development, it is not known how activated Ret receptor is trafficked in axons, the nature of the
transcriptional response induced by the retrograde Ret signaling, and how these transcriptional targets
ultimately promote axon growth. To address these questions, we are using the unique advantages of zebrafish,
including live imaging and genetic approaches, to identify the molecular mechanisms that govern retrograde
transport of a neurotrophin receptor Ret and the subsequent transcriptional response. In our preliminary
studies, we discovered that retrograde transport of Ret depends on binding to the scaffold protein, Jip3, which
links cargo to the retrograde motor for transport. Both ret and jip3 mutants display truncated sensory axons,
and live imaging revealed abnormal growth cone dynamics and reduced axon terminal elaboration. Using RNA
sequencing, we identified a number of factors that are transcriptionally induced in response to Ret-Jip3
retrograde signaling and are putative regulators of actin-based protrusive behavior in this context. Based on
this data, we hypothesize that Jip3-dependent retrograde transport of Ret induces factors that promote growth
cone dynamics required for sensory axon extension. We will test this hypothesis in the three specific aims. In
Aim 1, we will define the molecular mechanisms of Ret retrograde transport and the role of Jip3 in this process.
Experiments in the second aim will define the defects in growth cone dynamics that lead to the failure of axon
extension in ret and jip3 mutants and determine the role of the Ret retrograde signaling in this process. The
last aim will investigate the transcriptional response elicited by the retrograde Ret signaling and how factors
that are regulated by this transcriptional program promote growth cone dynamics. Altogether, our study
combines innovative assays in zebrafish with in vivo techniques to determine the specific role of retrograde
neurotrophin signaling in axon outgrowth. Our work will further uncover the mechanisms by which long-range
neurotrophin signals are transduced into cellular responses that regulate growth cone dynamics and axon
extension.

## Key facts

- **NIH application ID:** 10364762
- **Project number:** 5R01NS111419-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Alex Nechiporuk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $365,681
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364762

## Citation

> US National Institutes of Health, RePORTER application 10364762, Regulation of axon outgrowth by retrograde Ret signaling (5R01NS111419-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10364762. Licensed CC0.

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