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Systems approach to dissecting the processes underlying skeletal muscle fibre specification and morphogenesis


Warwick Medical School

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Dr T Saunders No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

This project is available through the MIBTP programme on a competition basis. The successful applicant will join the MIBTP cohort and will take part in all of the training offered by the programme. For further details please visit the MIBTP website - https://warwick.ac.uk/fac/cross_fac/mibtp/

Background: How does complex biological form emerge? Organs have specific shapes that are crucial for efficient function. Yet, the mechanisms underlying organogenesis remain poorly understood. Understanding these mechanisms has potential for wide impact, including in regeneration, wound healing and birth defects.

Vertebrate skeletal muscle formation is a highly conserved process. Each new segment (myotome) of muscle is generated in a clock-like fashion.1 Muscle fibres in the myotome can form multinucleated fast-twitch fibres or slow-twitch fibres. These fibres have different physiological properties. Over the past 25 years, the signalling molecules and networks that define these different cell populations have been identified.2

Recently, vertebrate-specific proteins have been discovered that drive muscle fibre multinucleation, e.g. Myomaker.3 Muscle fibres also rapidly undergo remarkable shape transformation, from nearly round to highly elongated. This leads to the following questions: (1) what are the interactions that ensure Myomaker and other fusion proteins are expressed in the correct cells at the right time; (2) can we correlate the genetic expression state of the cell with its mechanical state in the myotome; and (3) how does the developing myotome form so robustly?

Model system: Tackling these problems requires an in vivo model, as the whole system is important. We use zebrafish, which is easy to image during development and amenable to drug and genetic perturbations. This contrasts with mouse, where the developing embryo cannot be imaged in vivo. Zebrafish also lay eggs in large numbers, facilitating -omic approaches.

Project: We will combine the power of single cell sequencing4 with live imaging to tackle the above questions. In the first part, we will collaborate with Andrew Nelson and Sascha Ott at the single cell sequencing platform at Warwick to dissect the transcriptional state of the developing myotome. Recent advances in single cell sequencing enable accurate sequencing with relatively few samples (~ thousand cells). An advantage of the developing myotome is that it effectively has its own internal clock; each new myotome segment is specified 30 minutes (in zebrafish) after the preceding segment. Therefore, from sequencing neighbouring myotome segments we can extract temporal information about how the transcriptional state of the myotome evolves with time.

Using the sequencing results, we will generate maps of cellular states in both space and time. We will focus on cellular expression of Myomaker and other specific regulatory genes of myogenesis. We will complement analysis of wild-type embryos with suitable analysis of mutants that alter cell specification.2 Due to the internal clock of the developing skeletal muscle, these maps will have greater temporal resolution than those derived from typical single cell transcriptomic analysis.

In the second part, we will link the maps of cell fate to single cell tracking from live imaging. The Saunders lab can track the position and morphology of every cell within a developing myotome segment. By combining the cell transcriptional landscape with cell tracking, we will generate spatial and temporal predictions for potential targets that are crucial in the precise specification of different muscle fibre identities or morphologies. We will then perform targeted perturbations combined with live imaging to test these predictions. We aim to form novel insights into how skeletal muscle is generated in a robust manner.

Overall, this project is an exciting interdisciplinary project combining systems biology and live imaging which is suitable for a student looking to apply the latest systems biology approaches to a critical developmental system.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Systems Biology

Techniques that will be undertaken during the project:
• Single cell transcriptomics
• Computational systems biology
• Live microscopy imaging
• Image analysis and quantification
• Zebrafish husbandry and genetics

References

1 Soroldoni et al., Science 345, 222 (2014)

2 Jackson & Ingham, Mech Dev 130, 447 (2013)

3 Millay et al., Nature 499, 301 (2013)

3 Wagner & Klein, Nat Rev Gen 21, 410 (2020)
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