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P&F Grant Awards

Year 4

Grant # 6

Establishing A Novel Genetic Model System to Elucidate Conserved Mechanisms Controlling Adult Muscle Stem Cells

PI: Craig A. Micchelli, Ph.D.,


Specific Aims

The goal of the proposed investigation is to establish an experimental model to study stem cell-based control of adult muscle homeostasis in the genetically tractable system, Drosophila melanogaster. Many of the key cellular, molecular and physiological hallmarks of muscle biology are conserved between invertebrates and mammals (Augustin and Partridge, 2009). Therefore, if successful, our pilot study will pave the way for subsequent identification of conserved genes controlling the process of adult muscle homeostasis in vivo, using the unsurpassed molecular genetic screening methodologies available only in the fruit fly.
Adult tissue homeostasis often depends on a single cell type with the capacity to act as a reservoir of renewal potential, replacing old cells that are lost through injury or disease (Morrison and Spradling, 2008). Given the hierarchical organization inherent in stem cell lineages and the reiterative use of conserved signaling pathways in a lineage, it is essential to identify and manipulate adult stem cells with single cell resolution, in order to precisely dissect the molecular control of adult stem cells. However, due to their scarcity, adult stem cells in many tissues are often difficult to identify in vivo (Buckingham and Meilhac, 2011).
In the past few years, the adult fruit fly has emerged as a powerful model organism to identify and study a wide range of different adult stem cell types in their native microenvironments or “niches” using cutting edge molecular genetic methodologies (Casali and Batlle, 2009). These now include stem cells of the germ line, brain and gastrointestinal tract with subsequent studies demonstrating striking conservation in their regulation. Remarkably, however, adult muscle stem cells analogous to mammalian “satellite cells” have not yet been identified in adult Drosophila, despite the persistence of significant muscle mass into adulthood (e.g. flight muscles).
Here, we propose to build upon a unique set of resources and expertise that has accrued in my laboratory during the course of successfully identifying stem cells in other adult Drosophila tissues (Micchelli and Perrimon, 2006; Strand and Micchelli, 2011), to now test the hypothesis that myogenic stem cells maintain muscle homeostasis in the adult fruit fly. We propose to address the following specific aim in this pilot study:

Aim 1: We will determine the extent to which myogenic stem cells support adult muscle maintenance in the adult fruit fly, Drosophila melanogaster.

  • Aim 1A: Determine if adult muscles in Drosophila regenerate following injury.
  • Aim 1B: Distinguish whether or not the reservoir of renewal capacity in adult muscle resides in an undifferentiated myogenic stem cell compartment or among differentiated muscle cells.