To understand how the extraocular muscles (EOMs) control a wide range of eye movements, we must understand what controls the synthetic capacity of each muscle fiber and how that capacity defines the functional properties of that fiber. We have demonstrated that each of the myosin heavy chain (MyHC) isoforms is distributed into a specific domain of EOMs and - in some fibers - into a specific domain along the fiber. Most intriguing has been the demonstration of an EOM specific MyHC isoform only at the synaptic region of orbital singly innervated fibers with an embryonic isoform only in the extrajunctional regions. We hypothesize that the unusual distribution of MyHCs is largely responsible for the unique properties of EOMs and that there will be unique rules governing gene regulation in EOMs. Specifically, we hypothesize that a mechanism exists in EOMs for the synapse-specific synthesis of the extraocular isoform and for the extrajunctional specific synthesis of the embryonic isoform and that this mechanism is a pathway that leads from the central nervous system through the motoneuron to the MyHC genes. Using isoform specific antibodies and cDNA probes, we will assess the role of the motoneuron in the domain specific localization of MyHCs in EOMs. We will answer whether (a) there is differential synthesis of isoforms by synaptic versus subsynaptic nuclei; (b) the establishment of longitudinal variation during development is related to the maturation of the neuromuscular junction; (c) botulinum toxin treatment of strabismus disrupts the longitudinal variation of MyHCs and whether this rearrangement might be the mechanism by which botulinum toxin corrects static eye position; (d) molecules known to control the subsynaptic synthesis of other molecules are operable in the establishment and maintenance of longitudinal variation in MyHCs. We hope to establish a causal relationship between the organization of MyHC isoforms and the behavior of these atypical muscles and to establish a rationale for alternative surgical and pharmacological therapies of ocular motility disorders.
