# Assessing the contact-mediated role of netrin1 in axon guidance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $437,085

## Abstract

The establishment of neural circuits requires neurons to extend axons over considerable
distances, using molecular cues in the embryonic environment to orient their growth cones. The textbook
example of a guidance factor is netrin1, a member of the laminin superfamily first characterized in the spinal
cord. Classic studies suggested that netrin1, produced by floor plate (FP) cells, acts by chemotaxis, diffusing
over long distances to guide Dcc+ commissural axons towards the FP. Netrin1 was then implicated in
guidance decisions throughout the nervous system. However, our studies have recently demonstrated that the
key source of netrin1 is neural progenitor cells (NPCs) in the spinal ventricular zone. Rather than acting as a
long-range diffusible gradient, our data supports a model in which NPC-derived netrin1 acts locally, forming a
directional path for axons that also promotes axonal fasciculation. The bipolar geometry of NPCs permits them
to deposit netrin1 at the basal (pial) margins of the spinal cord. This netrin1+ substrate then acts locally to
direct fasciculated, ventral axon extension by haptotaxis, the directed growth of cells along an adhesive
surface. However, netrin1 may mediate a more complex activity for axons beyond pure adhesion: netrin1 is
then deposited onto Dcc+ axons, and these axons then grow precisely around the border of VZ, i.e. a netrin1-
expressing domain. Ablating a small region of netrin1 expression causes axons deviate from their trajectory to
follow the ectopic netrin1 boundary. We propose to call this collection of activities a “hederal” growth
boundary, from the analogy of a wall supporting the growth of ivy (genus: hedera) that is not itself penetrated
by the ivy. Netrin1 can form a local growth substrate, and promote the fasciculated growth of axons around a
netrin1-expressing domain. This reinterpretation of the mechanistic basis by which netrin1 functions, explains
why little progress has been made using soluble netrin1 as a regenerative factor. To further this goal, we will
assess [1] the mechanisms by which spinal NPCs establish a netrin1+ haptotactic substrate that promotes
directed, fasciculated axonal growth in Aim 1, [2] whether NPC vs FP cells have distinct roles producing netrins
in Aim 2 and [3] whether netrins have haptotactic activities in axon guidance in the forebrain in Aim 3.
Aim 1: Determine the mechanism by which spinal NPCs establish netrin1 “hederal” boundaries
Hypothesis: Spinal NPCs traffic netrin1 to the pial surface to establish a haptotactic substrate. Netrin1 then
transfers to Dcc+ axons to promote their fasciculated axon growth around netrin1-expressing regions.
Aim 2: Determine the range role of FP-derived netrin1 in the spinal cord
Hypothesis: FP-derived netrin1 acts over short range to fasciculate commissural axons crossing the midline
Aim 3: Determine the role of NPC-derived netrin1/3 in the forebrain
Hypothesis: Neural progenitors in the developing forebrain use the netrin family ...

## Key facts

- **NIH application ID:** 10663255
- **Project number:** 5R01NS107509-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** SAMANTHA J BUTLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $437,085
- **Award type:** 5
- **Project period:** 2019-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10663255

## Citation

> US National Institutes of Health, RePORTER application 10663255, Assessing the contact-mediated role of netrin1 in axon guidance (5R01NS107509-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10663255. Licensed CC0.

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