Skeletal muscles are not all created equal. Muscle precursor cells or myoblasts are not a homogeneous population with a preordained fate, but rather represent distinct lineages derived from a variety of embryonic sources. Extrinsic factors interact with lineage in sculpting the molecular/cellular/structural traits of developing myofibers. The extraocular muscles (EOMs) are particularly unique among skeletal muscles. Our central hypothesis is that development of the novel EOM phenotype relies upon cell autonomous and non-cell autonomous regulatory mechanisms that are both shared with and strikingly divergent from those determining myoblast fates in other skeletal muscles. Specifically, we propose that neural interactions unique to the orbital environment and signaling cascades controlled by tissue-specific transcription factors direct EOM expression of a diverse array of EOM-specific, skeletal, and cardiac muscle traits that adapt it to the wide dynamic physiologic range required by eye movement control systems. A central problem is that the wealth of data from 'traditional' muscle studies is insufficient to explain the patterning and specification of distinctive EOM properties. Our recent expression profiling studies and development of an EOM cell line have provided the knowledge and tools to now identify and directly test EOM regulatory mechanisms.
Specific Aim 1 will address cell autonomous regulatory mechanisms in EOM development, using immortialized EOM and hindlimb muscle cell lines in conjunction with gene/protein expression profiling.
Specific Aim 2 will examine the role of the transcription factor, Pitx2, in regulating early and late features of EOM development. An allelic series of Pitx2 mutant mice will be used to determine dose dependence in regulation of both general and fiber type-specific traits.
Specific Aim 3 will determine the role of a non-cell autonomous mechanism, unique to the orbital environment, in shaping EOM development. Our finding that EOM survival in organotypic co-culture is dependent upon oculomotor motoneuron innervation will be extended by assessing molecular specialization of EOM in culture with correct vs. incorrect motoneurons. The health relatedness of this proposal is that there is a clear need to understand the molecular specification of the EOM phenotype in order to comprehend both its unique functional features and differential responsiveness to metabolic and neuromuscular disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015306-04
Application #
7177461
Study Section
Special Emphasis Panel (ZEY1-VSN (04))
Program Officer
Agarwal, Neeraj
Project Start
2004-02-01
Project End
2007-05-31
Budget Start
2007-02-01
Budget End
2007-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$146,626
Indirect Cost
Name
Case Western Reserve University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Tao, Ye; Zhang, Min; Li, Lele et al. (2014) Pitx2, an atrial fibrillation predisposition gene, directly regulates ion transport and intercalated disc genes. Circ Cardiovasc Genet 7:23-32
Kusner, Linda L; Kaminski, Henry J (2012) The role of complement in experimental autoimmune myasthenia gravis. Ann N Y Acad Sci 1274:127-32
Zhou, Yuefang; Gong, Bendi; Kaminski, Henry J (2012) Genomic profiling reveals Pitx2 controls expression of mature extraocular muscle contraction-related genes. Invest Ophthalmol Vis Sci 53:1821-9
Kusner, Linda L; Young, Andrew; Tjoe, Steven et al. (2010) Perimysial fibroblasts of extraocular muscle, as unique as the muscle fibers. Invest Ophthalmol Vis Sci 51:192-200
Zhou, Yuefang; Liu, Dan; Kaminski, Henry J (2010) Myosin heavy chain expression in mouse extraocular muscle: more complex than expected. Invest Ophthalmol Vis Sci 51:6355-63
Zhou, Yuefang; Cheng, Georgiana; Dieter, Lisa et al. (2009) An altered phenotype in a conditional knockout of Pitx2 in extraocular muscle. Invest Ophthalmol Vis Sci 50:4531-41
Cheng, Georgiana; Kaminski, Henry J; Gong, Bendi et al. (2008) Monocular visual deprivation in macaque monkeys: a profile in the gene expression of lateral geniculate nucleus by laser capture microdissection. Mol Vis 14:1401-13
Soltys, Jindrich; Gong, Bendi; Kaminski, Henry J et al. (2008) Extraocular muscle susceptibility to myasthenia gravis: unique immunological environment? Ann N Y Acad Sci 1132:220-4
Kaminski, Henry J (2007) Restoring balance at the neuromuscular junction. Neurology 69:629-30
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

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