# Cellular and Molecular Mechanisms of Myotube Guidance

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $398,292

## Abstract

PROJECT SUMMARY
 The mechanisms that regulate skeletal muscle topography and perfectly align muscle morphology with the
overall body plan remain poorly understood. During embryonic development, muscle precursors known as
myotubes undergo a dramatic morphogenesis in which the myotube leading edges elongate, navigate to
tendons, and then choose pre-determined sites for muscle attachment. Myotube guidance refers to the
combined cellular processes of leading edge navigation and targeting decisions that connect muscles with the
correct tendons.
 We have used myogenesis in the Drosophila embryo as an entry point to identify the cellular and molecular
mechanisms of myotube guidance. Using forward genetic screens and genomics-based reverse genetics, we
identified multiple navigational signals that direct myotube leading edge migration, and uncovered transcription
factors that direct muscle morphogenesis. Our live imaging approaches revealed that myotubes actively
choose the correct muscle attachment site through a putative contact-dependent mechanism with tendon cells.
We hypothesize that the integrated actions of short-range navigational signals, morphogenetic gene regulatory
networks, and contact-dependent cell recognition programs direct myotube guidance to ensure muscle
topography perfectly complements the body plan.
 To achieve a comprehensive understanding of myotube guidance, we will investigate the interplay between
navigation, cell recognition, and gene regulatory modules. We propose (1) to investigate how multiple
navigational signals co-regulate the cytoskeleton to direct myotube leading edge migration, (2) to use
functional genomics to understand how a morphogenetic gene regulatory network modulates responses to
navigational signals and directs contact-dependent cell recognition, and (3) to uncover the heterophilic protein-
protein interactions between myotubes and tendon cells that establish a myotendinuos code. We expect the
foundational work proposed in this study will be a necessary first step toward understanding how navigational,
cell recognition, and gene regulatory modules cooperate to direct myogenesis in more complex systems and
human disease.

## Key facts

- **NIH application ID:** 10835036
- **Project number:** 5R01AR070299-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** AARON N JOHNSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $398,292
- **Award type:** 5
- **Project period:** 2016-09-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835036

## Citation

> US National Institutes of Health, RePORTER application 10835036, Cellular and Molecular Mechanisms of Myotube Guidance (5R01AR070299-08). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10835036. Licensed CC0.

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