# Regenerative and degenerative responses to axonal injury

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $453,070

## Abstract

Project Summary/Abstract:
Axons form connections between neurons over great distances in the brain and body, hence are vulnerable to
damage and stress. This project studies an evolutionarily conserved stress response pathway that becomes
activated in multiple scenarios of axonal damage and stress. The pathway, governed by the dileucine zipper
kinase DLK, known as Wallenda (Wnd) in Drosophila, engages structural plasticity mechanisms in neurons
that allow circuits to adapt to axon damage. These responses include axonal regeneration, neuronal death,
and, newly discovered in this project, synapse loss. The long-term goals of this project are (1) to understand
the mechanisms that lead to DLK signaling activation, and (2) to understand the cellular pathways that are
regulated by DLK. The project combines studies in both Drosophila and mice, focusing on motoneuron (MN)
responses to peripheral nerve injury (PNI). For the first goal, Aim 1 tests a hypothesis that DLK/Wnd signaling
is restrained by the presence of an intact synaptic connection, hence becomes activated following synapse
loss. The experiments build upon observations in complementary paradigms of synapse loss at Drosophila
neuromuscular junction (NMJ) synapse: (a) injuries to branched axons demonstrate that only complete
removal of all efferent connections are capable of activating Wnd signaling; (b) multiple cytoskeletal mutations
that lead to retraction and degeneration of NMJ synapses also lead to Wnd signaling activation. The proposed
experiments will distinguish how synaptic interactions intersect with the process of axonal transport to control
the activation of Wnd. Aim 2 studies the downstream responses regulated by DLK that enable structural
plasticity, and focuses on new phenotypes for DLK in the mouse spinal cord: the loss of synaptic inputs on the
cell bodies of axotomized MNs (termed `synaptic stripping') is dependent upon DLK function in MNs. In
addition, the recruitment of activated microglia to the MN cell body, which precedes the synapse loss, requires
DLK function in axotomized MNs. Aim 2 will test a hypothesis that DLK signaling gates the secretion of
molecular signals that recruit specific responses in microglia to facilitate synapse loss. The experiments will
evaluate the requirement of candidate secreted and immune molecules that were identified from a RiboTag
translational profiling approach to be strong targets of DLK regulation in axotomized MNs. The experiments will
also identify the microglial responses gated by DLK in axotomized MNs through single cell RNA-seq of isolated
microglia. Taken together, this work is expected to shed new light on neuron-microglial interactions relevant to
nervous system injury, and mechanisms structural plasticity and synapse loss through the specific lens of a
specific axonal damage signaling pathway.

## Key facts

- **NIH application ID:** 10679760
- **Project number:** 7R01NS069844-11
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** KENNETH M CADIGAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,070
- **Award type:** 7
- **Project period:** 2010-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10679760

## Citation

> US National Institutes of Health, RePORTER application 10679760, Regenerative and degenerative responses to axonal injury (7R01NS069844-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10679760. Licensed CC0.

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