# Converging molecular mechanisms in axon degeneration and astrocyte morphogenesis

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $429,000

## Abstract

SUMMARY
Astrocytes are one of the major glial subtypes of the central nervous system (CNS), evolutionarily conserved
from Drosophila to humans with regard to their morphology, molecular composition, and function. Although
their morphological complexity is thought to be essential for astrocytes to perform their myriad roles in the CNS
by physically contacting and interacting with diverse neural structures, including synapses and the vasculature,
we only know of a handful of pathways that critically regulate astrocyte morphology. From an unbiased,
forward genetic screen in Drosophila, we surprisingly identified dSarm and dWnk/Fray, both of which have
been implicated in axon degeneration, as potential new regulators of astrocyte morphology. Preliminary
findings in Drosophila show that dSarm/Sarm1 and dWnk/WNK work synergistically to regulate not only axon
degeneration but also astrocyte morphology. Here, we propose to leverage the larval zebrafish system to ask
whether the role of Sarm1 and WNK in regulating astrocyte development is evolutionarily conserved. In the
axon degeneration pathway, NAD+ depletion is thought to be upstream of dSarm/Sarm1 and dWnk/WNK
activation, and Axundead (Axed) to be downstream. Whereas the importance of NAD+ depletion upstream of
dSarm/Sarm1 and dWnk/WNK has been shown across species, the functional ortholog of Axed is unknown in
vertebrates. We therefore propose to determine if and how these known axon degeneration pathways up- and
downstream of dSarm/Sarm1 and dWnk/WNK also function in vertebrate astrocytes. By harnessing the
pharmacological and genetic toolkits available in larval zebrafish, we will interrogate the involvement of the
NAD+ biosynthetic pathway in controlling process dynamics and morphology of astrocytes in vivo. We will
additionally perform a targeted reverse genetic screen to identify the functional vertebrate ortholog of Axed in
mediating Sarm1/WNK effects on astrocyte morphology. Together, this study will define new roles for key
molecules in axon degeneration in the regulation of astrocyte morphogenesis and further our understanding of
the Sarm1 signaling pathway in vivo.

## Key facts

- **NIH application ID:** 10947696
- **Project number:** 1R21NS138718-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Kelly R Monk
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947696

## Citation

> US National Institutes of Health, RePORTER application 10947696, Converging molecular mechanisms in axon degeneration and astrocyte morphogenesis (1R21NS138718-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10947696. Licensed CC0.

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