# Molecular mechanisms of neuron motility and axon guidance

> **NIH NIH R56** · HARVARD MEDICAL SCHOOL · 2022 · $423,750

## Abstract

The brain relies for its function on a precise and complex pattern of neuronal connections. The broad long-term
goal of this project is to understand molecular mechanisms that set up this pattern of connections during
development, and how aberrations of this process lead to neurodevelopmental disorders.
 This proposal focuses particularly on RNA-based regulatory mechanisms. Key advantages of regulating
mRNA translation via RNA-binding proteins (RBPs) are: (1) allowing protein synthesis to be locally regulated in
specific subcellular regions where the proteins are needed, and (2) coordinately regulating expression of large
networks of functionally related mRNAs. To understand the basic principles of axon guidance, a major model
system has been spinal commissural axon guidance at the midline. Navigating this intermediate target requires
axons to be attracted and then repelled, and the classic mechanism for this is the `Robo switch' where
repellent Robo receptors are upregulated in post-crossing axons; however, the extracellular signal and the
mechanism by which it triggers this switch have been unknown. We have now identified a highly novel
mechanism for the Robo switch, involving extracellular ligand binding to the transmembrane Amyloid Precursor
Protein (APP), which interacts with the RBP CPEB4, to regulate Robo local translation in post-crossing axon
segments. This novel APP-CPEB4 pathway has high relevance to disease: in addition to the role of APP in
neurodegeneration, CPEB4 is currently of high interest as a cause of Autism Spectrum Disorder (ASD).
 The proposed studies continue our work on CPEB4, studying it in two developmental systems: (1)
Spinal commissural axon midline guidance. Expression of many proteins is known to be locally regulated in
axon segments at the midline, and the novel APP-CPEB4 pathway is likely to regulate not only Robo but other
proteins. This work is expected to show coordinate regulation of a large gene network at an intermediate target,
bringing together many disparate past observations into a unifying model for this major paradigm of axon
guidance. (2) Radially migrating neurons in the cerebral cortex. Abnormalities in this phase of development are
believed to be a leading cause of ASD. Based on existing evidence, CPEB4 regulates Robo expression in
developing cortex, and CPEB4 conditional disruption in mouse cortex at this specific stage causes ASD-like
behaviors. Compared to commissural axons, evidence indicates that CPEB4 regulates different processes in
cortical development. Studies of CPEB4 in cortical development will therefore uncover novel biological
principles, and will also directly inform the understanding of pathogenic mechanisms for ASD and other
neurodevelopmental disorders. Approaches include genome-wide target mRNA identification, and functional
developmental studies in vitro and in vivo. Additionally, studies of signal transduction mechanisms in the novel
APP-CPEB4 pathway will be essential to under...

## Key facts

- **NIH application ID:** 10626674
- **Project number:** 2R56NS069913-11
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** John G Flanagan
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,750
- **Award type:** 2
- **Project period:** 2011-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10626674

## Citation

> US National Institutes of Health, RePORTER application 10626674, Molecular mechanisms of neuron motility and axon guidance (2R56NS069913-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10626674. Licensed CC0.

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