# Molecular genetics of axon and synapse development and maintenance

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $836,800

## Abstract

Project Summary
The goals of my research program are to elucidate fundamental mechanisms underlying synapse and
axon development and maintenance. We take multi-tiered approaches to investigate these processes,
primarily using C. elegans because this animal model is well suited for in vivo imaging with high cellular
resolution and because mechanistic dissection is within physiological relevant contexts and coupled
with functional impacts. We examine the C. elegans locomotor circuit, because we can unambiguously
observe the stereotyped patterns of synapses in all developmental stages, an essential readout to
assess how synapses are dynamically regulated. We have consistently developed innovative
technologies enabling visualization of organelles and subcellular structures in axons and synapses for
in vivo analyses of dynamic cellular processes. We were the first to visualize synapse remodeling of
juvenile motor circuit in living animals, which set two decades of vibrant research that have revealed
multiple pathways coordinating temporal events and spatial organization of synaptic connections. We
established C. elegans axon regeneration model, and have used large-scale genetic screens to
discover genes that promote or repress axon regrowth in adults. Many pathways have been found to
have conserved roles in axon regeneration in other animal models. In this R35 application, we will
focus on mechanisms underlying both the developmental synapse plasticity in locomotor circuit
maturation and maintenance, and also neuronal stress response and axon regeneration in adults. We
will investigate how neuronal activity pattern coordinates with transcriptional regulation by combining in
vivo imaging of synapse and calcium with single-cell RNA sequencing analysis over the entire period of
circuit remodeling. We will gain a deep understanding of molecular dynamics associated with synapse
and circuit plasticity. We have long-standing interest in the multifaceted roles of the conserved MAP3K
DLK proteins, which have been shown to regulate diverse cellular processes from synapse formation
and remodeling to axon regeneration and neurodegeneration. We will cross-examine mechanistic
conservation between C. elegans and mice. Membraneless compartments generated through protein
phase separation are now widely shown to play key roles in organizing cellular activities, including axon
regeneration. We will take a holistic approach to investigate protein phase separation with
physiological relevant expression and contexts, and also to model how genetic mutations in human
homologs may alter protein phase separation properties. Overall, the findings will advance our
knowledge on the cellular signaling network underlying normal brain function and will also provide
insights into pathological processes associated with synapse dysfunction and axonal damage.

## Key facts

- **NIH application ID:** 10821490
- **Project number:** 5R35NS127314-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Yishi Jin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $836,800
- **Award type:** 5
- **Project period:** 2022-05-01 → 2030-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821490

## Citation

> US National Institutes of Health, RePORTER application 10821490, Molecular genetics of axon and synapse development and maintenance (5R35NS127314-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10821490. Licensed CC0.

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