Development of the vertebrate musculoskeletal system requires the coordinated morphogenesis of muscle, muscle connective tissue, tendon, and skeleton. In the limb, muscle derives from migratory precursors originating from the somites, while the muscle connective tissue, tendons and skeletal elements derive from the mesoderm of the emerging lateral-plate derived limb bud. As the muscle precursors migrate into the limb, they must differentiate into myofibers, become correctly patterned into distinct anataomical muscles, and be assemebled into a functional musculoskeleton. How the over 40 limb muscles are patterned and muscle and muscle connective tissue morphogenesis coordinated is the subject of this proposal. Classical studies had suggested that lateral plate, limb mesodermal signals are important patterning muscle. However, neither the molecular nature of the signal nor the tissue producing it was known. Recently we have identified a population of lateral plate, limb mesodermal cells that expresses the transcription factor Tcf4, a downstream effector of the Wnt/beta-catenin signaling pathway, and that is critical for muscle patterning. Functional studies in the chick suggest that Tcf4-expressing cells establish a prepattern in the limb mesoderm that determines where muscle precursors differentiate and thus where individual muscles will form and the ultimate limb muscle pattern. In addition, preliminary studies indicate that Tcf4-expressing cells are the precursors of the muscle connective tissue, a tissue of fundamental importance to the form and function of the musculoskeleton and whose development has been largely unstudied because of the lack of early molecular markers. We propose to test genetically in the mouse the role of limb mseodermal Tcf4- expressing cells and Wnt/beta-catenin signaling in determining the pattern of limb muscles. In addition, we will determine whether Tcf4-expressing cells are precursors necessary for formation of muscle connective tissue. These experiments will provide important insights into the normal development of muscle and muscle connective tissue and the role of Wnt/beta-catenin signaling in regulating their development. Disruptions in the development of muscle and muscle connective tissues can result in severe musculoskeltal disorders, such as Duchenne's muscular dystrophy and Ullrich congenital muscular dystrophy. Results from our experiments will give us important new insights into the etiology of these diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD053728-05S1
Application #
8089982
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Javois, Lorette Claire
Project Start
2010-07-10
Project End
2012-06-30
Budget Start
2010-07-10
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$77,704
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Domyan, Eric T; Kronenberg, Zev; Infante, Carlos R et al. (2016) Molecular shifts in limb identity underlie development of feathered feet in two domestic avian species. Elife 5:e12115
Kikani, Chintan K; Wu, Xiaoying; Paul, Litty et al. (2016) Pask integrates hormonal signaling with histone modification via Wdr5 phosphorylation to drive myogenesis. Elife 5:
Colasanto, Mary P; Eyal, Shai; Mohassel, Payam et al. (2016) Development of a subset of forelimb muscles and their attachment sites requires the ulnar-mammary syndrome gene Tbx3. Dis Model Mech 9:1257-1269
Merrell, Allyson J; Ellis, Benjamin J; Fox, Zachary D et al. (2015) Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nat Genet 47:496-504
Pawlikowski, Bradley; Pulliam, Crystal; Betta, Nicole Dalla et al. (2015) Pervasive satellite cell contribution to uninjured adult muscle fibers. Skelet Muscle 5:42
Keefe, Alexandra C; Lawson, Jennifer A; Flygare, Steven D et al. (2015) Muscle stem cells contribute to myofibres in sedentary adult mice. Nat Commun 6:7087
Murphy, Malea M; Keefe, Alexandra C; Lawson, Jennifer A et al. (2014) Transiently active Wnt/?-catenin signaling is not required but must be silenced for stem cell function during muscle regeneration. Stem Cell Reports 3:475-88
Lours-Calet, Corinne; Alvares, Lucia E; El-Hanfy, Amira S et al. (2014) Evolutionarily conserved morphogenetic movements at the vertebrate head-trunk interface coordinate the transport and assembly of hypopharyngeal structures. Dev Biol 390:231-46
Rohatgi, Anjali; Corbo, Joseph C; Monte, Kristen et al. (2014) Infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of chikungunya virus. J Virol 88:2414-25
Merrell, Allyson J; Kardon, Gabrielle (2013) Development of the diaphragm -- a skeletal muscle essential for mammalian respiration. FEBS J 280:4026-35

Showing the most recent 10 out of 17 publications