Investigating a zebrafish model of rare human muscle disease

Supervisor: Dr. Sabine Costagliola

Centronuclear myopathies (CNM) are a group of rare and early-onset genetic muscle disorders for which no curative treatment is available. This fatal condition is linked to mutations in several genes including myotubularin (MTM1). Mutations in this gene cause the X-linked myotubular myopathy, which is the most frequent and severe form of CNM. In CNM, several defects have been observed at the cellular level, such as abnormal triad structure and dysfunctional excitation-contraction coupling, crucial for skeletal muscle contraction.

In our lab, we have translated the human disorder to the zebrafish model system by generating several mtm1 mutants using CRISPR/Cas9 technology. The mutants exhibit progressive appendage (fin fold) degeneration, defective motor behavior and early mortality. The PhD candidate will analyze the muscular ultrastructure changes in the mutant model.

Our objectives are:

  1. To understand the contribution of mtm1 in muscle integrity in normal condition or upon muscle injury.
  2. To identify by single-cell RNAseq genes differentially regulated in muscle, stem cells and stroma of mtm1 mutants.
  3. To rescue the early lethal phenotype by mtm1 wt mRNA injection in mtm1 mutant embryos to allow the study of muscle integrity in adult fish.
  4. To study the phenotype of mtm1 -/- muscle cells integrated in muscle of WT fish (cell transplantation before gastrulation).
  5. To understand the mechanism involved in epithelial appendage (fin fold) degeneration in mtm1 mutants.

For this, the PhD candidate will learn genomics, next-generation RNA-sequencing, immunohistochemistry, live imaging, cell biology and regenerative biology. Most importantly, the candidate will take part in translating rare human conditions to animal models.

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