# Cellular and Molecular Mechanisms of Myotube Pathfinding

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $335,500

## Abstract

Project Summary
 Congenital myopathies (CM) are a heterogeneous collection of disorders defined by early onset
hypotonia. Some myopathies can progress to extreme conditions in which patients develop
respiratory complications and even require assistance for mobility. Mutations in genes associated
with actin dynamics have been identified in patients with CMs, including Tropomyosins. We found
that Drosophila Tropomyosin 2 (Tm2) directs embryonic skeletal muscle development by promoting
myoblast fusion, myotube elongation, and sarcomere assembly. These surprising results argue that
defects in myofiber development contribute to the clinical phenotypes associated with CMs.
 There remain critical knowledge gaps in our understanding of skeletal muscle development. In
particular, nascent myotubes must elongate and attach to the appropriate tendon cells to form a
functional contractile unit. However, the molecules that guide myotubes to their muscle attachment
sites remain largely unknown. In addition, the mechanisms by which myotubes respond to
chemotactic signals are unclear. We have used forward genetic screens and cutting edge
transcriptional profiling to identify myotube guidance molecules and intracellular effectors of myotube
elongation. Our preliminary work has generated unique genetic tools and novel mechanistic insights
that will allow us to characterize the central pathways and mechanisms that direct myotube
elongation. The overall hypothesis for this application is that filopodia are the key effectors of
myotube pathfinding, and that filopodial behavior is dictated by external pathfinding cues, intracellular
protein kinases, and actin regulatory proteins. This project will achieve the following aims: (1) define
the cellular pathways by which Tropomyosin regulates myogenesis, (2) characterize novel
intracellular effectors of myotube pathfinding, and (3) characterize chemotactic mechanisms that
direct myotube pathfinding. These studies will make substantial inroads into an emerging area of
muscle biology that has the potential to uncover novel mechanisms that contribute to muscle disease.

## Key facts

- **NIH application ID:** 9999412
- **Project number:** 5R01AR070299-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** AARON N JOHNSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,500
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999412

## Citation

> US National Institutes of Health, RePORTER application 9999412, Cellular and Molecular Mechanisms of Myotube Pathfinding (5R01AR070299-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999412. Licensed CC0.

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