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Date of Award

2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Supervisor

Dr. Michael A. Rudnicki

Abstract

The myogenic regulatory factors (MRFs) are crucial for the determination and terminal differentitation of the skeletal muscle lineage. Gene targeting experiments have demonstrated that one of MyoD or Myf5 is required for establishing the myogenic lineage in vivo. To further understand the role of MyoD in lineage acquisition and differentiation, fibroblast cell lines lacking functional copies of MyoD and Myf5 were generated and analyzed. The data shows that myogenin and MRF4 are capable of supporting terminal differentiation while at least one of MyoD of Myf5 is required for maintenance of myoblast indentity. This represents the first direct evidence that maintenance of the myogenic lineage absolutely requires MyoD or Myf5. While expression of the MRFs is necessary for myogenesis, several extracellular growth factor stimulation leads to the activation of several intracellular signal transduction pathways. To understand the role of the mitogen-activated protein kinase (MAPK) pathway in regulating MRF function, experiments were performed to specifically address the effects of the MAPK signaling intermediate, MEK1. The data clearly shows that transcriptional activity of the MRFs is repressed when the MAPK pathway is activated. Repression of MyoD function occurs in the absence of direct MAPK phosphorylation, alterations in MyoD stability or subcellular localization. Remarkably, activated MEK1 localizes to the nucleus and binds directly to a transcriptional complex containing MyoD and its dimerization partner HEB. This data represents the first description of how the MAPK pathway controls myogenesis without suppressing the myoblast lineage. Data also revealed a critical cell cycle-specific loss of HEB as an additional regulatory mechanism for controlling myogenesis.

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