Vertebrate skeletal muscles contain muscle fibers of several types that can be broadly classified as slow or fast on the basis of differences in contraction speed, metabolic activity, and motoneuron innervation. The long term goal of this project is to understand the genetic mechanisms that regulate muscle cell fates - which fiber types muscle precursors form. The first muscle fibers form in the somites of the embryo. Signals from adjacent tissues induce the fates of cells in the somites, including muscle. The proposed studies will characterize this inductive signaling in zebrafish embryos with 3 specific aims: 1. To test the hypothesis that local signals from axial mesoderm specify muscle precursors to form slow rather than fast muscle. (a) Test whether local signaling from axial mesoderm is sufficient to specify the slow muscle fate by transplanting individual fast muscle precursors into the slow muscle precursor position and by transplanting notochord precursor cells into the fast muscle position. (b) Test whether local signaling from axial mesoderm is necessary to specify the slow muscle fate by transplanting individual slow precursors into the fast position. By transplanting cells at various developmental times, these experiments will show when and where muscle precursors are committed to specific fates and the role of local signaling from axial mesoderm. 2. To test the hypothesis that Hedgehog and TGF family members provide competing inductive and inhibitory signals to establish the muscle pioneer cell fate. (a) Test whether endogenous signals inhibit formation of muscle pioneers by transplanting putative inhibitory cells into the slow precursor position. Test whether Radar, a TGF, (b) inhibits the formation of muscle pioneers, (c) blocks the action of Hedgehog, and (d) is required for muscle pioneer patterning. These experiments will establish the role of a putative negative regulator of the muscle pioneer cell fate. 3. To identify genes that regulate specification of muscle cell fates. (a) Examine existing mutations for ones that alter slow muscle, fast muscle, or muscle pioneer cell fates. (b) Identify new genes by screening specifically for mutations that alter the formation or patterning of the three muscle cell types. These experiments will identify the genes that regulate muscle cell-type specification and differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045575-04
Application #
6497440
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Lymn, Richard W
Project Start
1999-02-05
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
4
Fiscal Year
2002
Total Cost
$268,733
Indirect Cost
Name
University of Oregon
Department
Other Basic Sciences
Type
Organized Research Units
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
Ochi, Haruki; Westerfield, Monte (2009) Lbx2 regulates formation of myofibrils. BMC Dev Biol 9:13
Ochi, Haruki; Hans, Stefan; Westerfield, Monte (2008) Smarcd3 regulates the timing of zebrafish myogenesis onset. J Biol Chem 283:3529-36
Nixon, Susan J; Carter, Adrian; Wegner, Jeremy et al. (2007) Caveolin-1 is required for lateral line neuromast and notochord development. J Cell Sci 120:2151-61
Chen, Yau-Hung; Wang, Yun-Hsin; Chang, Min-Yen et al. (2007) Multiple upstream modules regulate zebrafish myf5 expression. BMC Dev Biol 7:1
Ochi, Haruki; Pearson, Bret J; Chuang, Pao-Tien et al. (2006) Hhip regulates zebrafish muscle development by both sequestering Hedgehog and modulating localization of Smoothened. Dev Biol 297:127-40
Nixon, Susan J; Wegner, Jeremy; Ferguson, Charles et al. (2005) Zebrafish as a model for caveolin-associated muscle disease; caveolin-3 is required for myofibril organization and muscle cell patterning. Hum Mol Genet 14:1727-43
Wiellette, Elizabeth; Grinblat, Yevgenya; Austen, Matthias et al. (2004) Combined haploid and insertional mutation screen in the zebrafish. Genesis 40:231-40
Hirsinger, Estelle; Stellabotte, Frank; Devoto, Stephen H et al. (2004) Hedgehog signaling is required for commitment but not initial induction of slow muscle precursors. Dev Biol 275:143-57
Varga, Z M; Amores, A; Lewis, K E et al. (2001) Zebrafish smoothened functions in ventral neural tube specification and axon tract formation. Development 128:3497-509
Barresi, M J; Stickney, H L; Devoto, S H (2000) The zebrafish slow-muscle-omitted gene product is required for Hedgehog signal transduction and the development of slow muscle identity. Development 127:2189-99

Showing the most recent 10 out of 11 publications