# Cellular and molecular mechanisms of peripheral nerve regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $385,674

## Abstract

The peripheral nervous system has retained a remarkable capacity for axonal regeneration. In response to
injury, well-characterized neuron intrinsic signaling pathways mount a regenerative response that eventually
leads to spouting of axonal growth cones. Promoted by well-defined growth factors, growth cones extend along
denervated Schwann cells that they utilize as a general regeneration pathway, yet at branch points individual
regenerating axons have to select the correct path towards their original targets. Although accurate
regeneration of axons to their original targets is critical for the functional recovery, the cellular and molecular
mechanisms by which regenerating axons select their original targets are not well understood.
 We recently established an in vivo system to monitor and quantify target selective re-innervation in live
intact animals. Using this system we discovered that following transection of the dorsal and ventral motor nerve
branch, regenerating zebrafish motor axons exhibit a strong preference for their original muscle territory,
providing compelling evidence for the existence of molecular mechanisms for target-selective regeneration. To
identify the genes underlying this process we surveyed mutants in genes with known roles in neural
development. We identified four genes that do not promote axonal regrowth per se, but rather provide target
selectivity to regenerating axons. The experiments in this proposal build upon the findings that in mutants for
the robo2 guidance receptor and for the exostosin like 3 (extl3) glycosyltranferase motor axons develop normal
but regenerating dorsal nerve axons frequently select incorrect, ectopic trajectories, invading lateral and ventral
territories. While both genes play well-defined roles in neural development, their function in regeneration is not
understood. The experiments in this proposal will define the mechanisms by which these two genes promote
target selective regeneration. In Aim 1 we will determine the molecular mechanisms through which robo2
functions in regeneration, e.g. as an axonal Slit receptor, or alternatively as Schwann cell receptor. In Aim 2 we
will determine the cellular mechanisms by which robo2 guides dorsal nerve regeneration, e.g. by correcting
pathfinding mistakes at the choice point, and/or by directing pioneering axons towards their original path,
thereby providing a regeneration pathways for follower axons. Finally, in Aim 3 we will determine whether
exostosin like 3 (extl3) guides regenerating axons through its role in heparan sulfate production or via its
unique surface receptor domain. Combined, the proposed studies will make significant contributions to the
fundamental science of how transected axons return to their original targets. This will results in a better
understanding of peripheral nerve regeneration across the board and will help to address the urgent
therapeutic needs for patients suffering from peripheral neuropathies.

## Key facts

- **NIH application ID:** 9948761
- **Project number:** 5R01NS097914-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Granato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,674
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948761

## Citation

> US National Institutes of Health, RePORTER application 9948761, Cellular and molecular mechanisms of peripheral nerve regeneration (5R01NS097914-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948761. Licensed CC0.

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