Proposed studies continue long-term efforts to understand.extraocular muscle (EOM). The diversity and plasticity that is inherent in eye movement control systems is reflected in the unusual characteristics of EOM. Traditional concepts regarding the regulation of muscle morphology, physiology, and gene expression then may be different for EOM. Collectively, these studies address the hypothesis that properties of EOM are the result of the interaction of nerve-dependent and nerve-independent developmental mechanisms acting together with the functional demands placed upon these muscles by diverse motor control systems.
Specific Aim 1 is designed to describe events in the prenatal and postnatal development of rat EOM, as they relate to the establishment of motor innervation and to the onset of purposeful eye movements. Rat EOM development will be studied using morphologic (light and electron microscopy) and cellular/molecular (myosin heavy chain immunocytochemistry and in situ hybridization) approaches to correlate the spatial/temporal patterns in development of fiber morphology and myosin expression with the maturation of neuromuscular junctions and onset of oculomotor function.
Specific Aim 2 will assess myofiber morphogenesis in an organotypic co-culture model that pairs either appropriate (oculomotor) or inappropriate (spinal) motoneurons with EOM primordia. Pilot data using this model indicate that the survival of EOM in organotypic co-culture with neural tissue may be dependent upon innervation by the appropriate oculomotor motoneurons, and that no other motoneurons will suffice. These studies will characterize (a) morphogenesis and degeneration in organotypic co- cultures of EOM with spinal motoneurons that fail to survive beyond 3 weeks and (b) the developmental stages attained in co-cultures of EOM with oculomotor motoneurons that may survive long term.
Specific Aim 3 will identify the mechanisms that promote the survival of EOM in organotypic coculture. Specifically, the design (a) examines the potential of several defined growth factors, that have been shown to either regulate myogenesis (bFGF, IGF-I, IGF-II) or block programmed neuronal death (CNTF), for the ability to promote EOM survival in organotypic culture and (b) determines the influence of patterned neural activity upon explant survival via pharmacological denervation of co-cultures of EOM with oculomotor motoneurons. Collectively, proposed studies will address the specific developmental mechanisms that make EOM different from all other skeletal muscles. Although disorders in oculomotility can have a devastating impact during the critical period of visual system development, descriptions and experimental studies of mechanisms responsible for EOM development (and maldevelopment) are lacking. In this respect, the proposed studies can aid understanding of the broader issue that muscle dysfunction may play a role in the developmental disorders of congenital strabismus and amblyopia.
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