The extraocular muscles (EOMs) are uniquely specialized to maintain interocular alignment and coordinate eye movements. The rapid saccades and slow pursuit movements they enable differ fundamentally from the twitch responses of limb muscles, and these differences are reflected in the morphology, innervation, and patterns of contractile proteins expression that distinguish EOM fibers. These studies will establish direct relationships between the maturation of the oculomotor system, EOM fiber physiology, and contractile protein and myogenic factor expression. Because myosin defines the primary features of muscle fiber phenotype in most skeletal muscles, it has been a major focus of EOM studies. The complex and promiscuous patterns of myosin expression found in EOM suggest that EOM fibers may be arrested at the neonatal/adult transition. It is more likely that the specialized properties of EOM fibers are determined by an integrative mechanism that controls movement by tightly regulating thin filament activation and intracellular calcium concentrations. To test this hypothesis, EOM-specific myosin will be purified and characterized, and the effects of different patterns of myosin expression will be determined for individual EOM fibers. In addition, the molecular characterization of the developmental state of the EOMs will be extended to the excitation-contraction coupling and sarcoplasmic calcium reuptake systems, as these seem to play important roles in determining the rapid contraction times and shortening velocity of EOM fibers. Determining the isoforms of these proteins expressed in EOM will provide an additional test of the developmental arrest hypothesis. With the understanding of muscle protein expression gained from these studies, the developmental transitions of EOM contractile proteins will be characterized to determine whether they are preprogrammed or are related to the postnatal maturation of the oculomotor system. As part of these studies, the patterns of expression of myogenic regulatory factors in EOM will be characterized to determine whether they might be related to the novel physiological properties of EOMs. The understanding of EOM development and plasticity gained by this integrated molecular, developmental, and physiological approach will define the regulation of normal EOM development and provide an understanding of the maldevelopment and genetic deficiencies that result in congenital strabismus and amblyopia.
