# Regulation of Growth Cone Polarity and Protrusion in Axon Guidance

> **NIH NIH R03** · UNIVERSITY OF KANSAS LAWRENCE · 2020 · $140,660

## Abstract

Understanding the effects of guidance cues and their receptors on the growth cone during outgrowth will be
critical to a comprehensive understanding of axon guidance in normal and diseased states. The Netrin family
of secreted guidance cues act as both attractants and repellants in axon guidance. By analyzing the effects
of mutations in Netrin signaling on the growth cone during outgrowth, we have developed a new model
of Netrin mediated control of directed growth cone migration called the polarity/protrusion model. Our
results using live growth cone imaging indicate that UNC-6/Netrin signaling, via the UNC-5 receptor, polarizes
protrusion and F-actin in growth cones, resulting in dorsal protrusion away from the ventral UNC-6/Netrin
source. We found that Netrin also inhibits protrusion ventrally via UNC-5, and stimulates protrusion dorsally
via the Netrin receptor UNC-40, based on growth cone polarity (Figure 1). Thus, UNC-6/Netrin signaling both
polarizes the growth cone, and regulates the extent of protrusion based on this polarity. By inhibiting protrusion
ventrally and stimulating protrusion dorsally, Netrin drives directed growth dorsally away from the UNC-6/Netrin
source. A key ramification of this model is that UNC-6/Netrin receptor function will be distributed
asymmetrically across the growth cone, with UNC-5 inhibitory activity localized ventrally and UNC-40
stimulatory activity localized to the dorsal area of the growth cone. We will test this key aspect of the
polarity/protrusion model by assaying Netrin receptor localization in growth cones.
Significance: These studies will significantly advance understanding of axon guidance, as they invoke and test
a fundamentally novel model of directed growth cone migration in axon guidance, the polarity/protrusion model.
In this new model, UNC-6/Netrin polarizes the growth cone such that the asymmetric activity of both pro- and
anti-protrusive forces, each controlled by UNC-6/Netrin in the same growth cone, lead to directed migration
away from UNC-6/Netrin. Our results, combined with studies in vertebrates showing that floorplate Netrin is
dispensable for commissural axon guidance, suggest a new model of axon guidance involving regulation of
growth cone polarity and protrusion.

## Key facts

- **NIH application ID:** 9872710
- **Project number:** 1R03NS114554-01
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Erik A Lundquist
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $140,660
- **Award type:** 1
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872710

## Citation

> US National Institutes of Health, RePORTER application 9872710, Regulation of Growth Cone Polarity and Protrusion in Axon Guidance (1R03NS114554-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9872710. Licensed CC0.

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