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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY009834-01A1
Application #
3267179
Study Section
Special Emphasis Panel (ZRG1-VISB (01))
Project Start
1993-07-01
Project End
1996-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Porter, John D; Israel, Sheri; Gong, Bendi et al. (2006) Distinctive morphological and gene/protein expression signatures during myogenesis in novel cell lines from extraocular and hindlimb muscle. Physiol Genomics 24:264-75
Spencer, Robert F; Porter, John D (2006) Biological organization of the extraocular muscles. Prog Brain Res 151:43-80
Zhou, Lan; Porter, John D; Cheng, Georgiana et al. (2006) Temporal and spatial mRNA expression patterns of TGF-beta1, 2, 3 and TbetaRI, II, III in skeletal muscles of mdx mice. Neuromuscul Disord 16:32-8
Khanna, Sangeeta; Cheng, Georgiana; Gong, Bendi et al. (2004) Genome-wide transcriptional profiles are consistent with functional specialization of the extraocular muscle layers. Invest Ophthalmol Vis Sci 45:3055-66
Porter, John D; Merriam, Anita P; Leahy, Patrick et al. (2004) Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy. Hum Mol Genet 13:257-69
Cheng, Georgiana; Merriam, Anita P; Gong, Bendi et al. (2004) Conserved and muscle-group-specific gene expression patterns shape postnatal development of the novel extraocular muscle phenotype. Physiol Genomics 18:184-95
Porter, John D; Merriam, Anita P; Leahy, Patrick et al. (2003) Dissection of temporal gene expression signatures of affected and spared muscle groups in dystrophin-deficient (mdx) mice. Hum Mol Genet 12:1813-21
Cheng, Georgiana; Mustari, Michael J; Khanna, Sangeeta et al. (2003) Comprehensive evaluation of the extraocular muscle critical period by expression profiling in the dark-reared rat and monocularly deprived monkey. Invest Ophthalmol Vis Sci 44:3842-55
Andrade, Francisco H; Merriam, Anita P; Guo, Wei et al. (2003) Paradoxical absence of M lines and downregulation of creatine kinase in mouse extraocular muscle. J Appl Physiol 95:692-9

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