Characterization of the mechanisms regulating the differentiation of embryonic stem cells into functional motoneurons

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The simple act of walking requires the activation of over 200 muscles in the human body. Each muscle is controlled, and thus innervated, by dozens of motoneurons that are anatomically segregated within distinct regions(called motoneuron pools) of the spinal cord. Walking movements are smooth because motoneurons innervating the legs are activated in a very precise manner throughout the step cycle. In addition, different subtypes of motoneurons and muscle fibers are responsible for different aspects of locomotion. Standing and slow movements are control by motoneurons and muscles fibers that differ anatomically and physiologically from those controlling heavy lifting and fast running. While the neuromuscular system can be modulated by activity throughout life, most of the physiological and anatomical properties regulating movements are established by birth. The long-term objective of my research program is to better understand how these physiological and anatomical properties are established during embryonic development and re-established after nerve injury. The short-term aim of this grant proposal is to investigate 1) how specific type of motoneurons are formed in the developing spinal cord during embryonic development, and 2) how these motoneurons selectively grow to specific muscles in the body. To achieve this aim, we will use embryonic stem cells that were differentiate into motoneurons. These behavior of these stem cell derived motoneurons will be studied in culture, and in the developing chick embryo, in order to investigate the molecular mechanisms regulating their growth and differentiation.