# Molecular mechanisms of neuron motility and axon guidance

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $383,585

## Abstract

The brain relies for its function on a precise and complex pattern of axonal connections. The broad long-term
goal of this project is to understand how this pattern of axon connections is set up during development. When
such connections fail to form properly, or are subsequently lost, this can lead to a broad range of
neurodevelopmental, psychiatric and neurodegenerative disorders.
This proposal focuses particularly on RNA-based regulatory mechanisms. A key advantage of regulating gene
expression at the mRNA level is that protein expression can be directed to specific subcellular regions with
temporal and spatial specificity – an important advantage in neurons, which have a high degree of spatial
organization. Accordingly, RNA-based regulation plays key roles in axon guidance, neuron migration and
synapse plasticity, although the specific mechanisms remain poorly understood. Here, RNA-based
mechanisms will be studied in regulation of the microtubule cytoskeleton (Aim 1), and in axon pathway
selection at a complex choice point (Aim 2). Aim 1 focuses on the microtubule cytoskeleton, which has crucial
roles in neuron structure and motility. Our recent work has now identified a mechanism for RNA-based
regulation of microtubules. Specifically, microtubule plus-end protein APC binds tubulin Tubb2b mRNA, at a
site required for Tubb2b translation in axons, formation of dynamic microtubules in the growth cone, and
neuron migration in vivo. This opens up a new field of investigation into RNA-based regulation of the
microtubule cytoskeleton. One goal will be to investigate coordinated regulation of specific tubulin mRNAs
which have APC binding sites in their 3'UTR and cause most human tubulinopathies. Another objective will use
time-lapse imaging to understand specifically how RNA-based regulation controls microtubule dynamics,
including fundamental new models for both microtubule initiation at the minus end, and assembly at the plus-
end. In addition to axons, these mechanisms will be characterized in formation of synaptic spines. Aim 2 will
continue studies of commissural axon guidance at the spinal cord midline, a well-characterized model of
developmental axon pathfinding. RNA-based regulation is known to occur within commissural axons, including
upregulated translation of mRNAs in distal axon segments that have crossed the midline intermediate target.
However, little has been known of the mechanisms, including the RNA-binding proteins involved, their
downstream mRNA targets, or upstream regulatory pathways. This Aim will characterize specific RNA-binding
proteins that display highly selective expression on axon segments, strong and distinct phenotypes in midline
guidance, and interactions with mRNAs regulated in axons at the midline; as well as upstream ligands and
receptors that interact physically and functionally with these RNA based regulatory mechanisms. These studies
will provide novel information on fundamental mechanisms of axon development, and...

## Key facts

- **NIH application ID:** 9904764
- **Project number:** 5R01NS069913-10
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** John G Flanagan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,585
- **Award type:** 5
- **Project period:** 2011-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904764

## Citation

> US National Institutes of Health, RePORTER application 9904764, Molecular mechanisms of neuron motility and axon guidance (5R01NS069913-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9904764. Licensed CC0.

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