Genetic regulation of muscle fiber diversity. Abstract. The long-term objective of our research is to define the factors which regulate differentiation of the diverse skeletal muscle types which are found in animals. Distinct muscle fiber-types are specified in order to engender muscles with specialized characteristics, yet the molecular underpinnings of this specification process have yet to be defined. The Drosophila system has proven useful in defining mechanisms of muscle specification and muscle differentiation, and in addition the Drosophila adult thorax contains skeletal muscle fibers of two distinct types. We therefore propose to define the molecular bases of development for the adult Drosophila muscles, with the expectation that the processes that we uncover will contribute important new information into skeletal muscle developmental mechanisms, and will also define how distinct muscle fiber phenotypes arise. In the current period of funding, we have begun to define in detail how the regulatory factor Myocyte enhancer factor-2 (MEF2) controls muscle development in the Drosophila adult. While our data indicate an important requirement for MEF2 in adult myogenesis, we also found that a large number of adult muscle- specific structural genes are regulated independently of MEF2. In this application we plan to connect MEF2 function to adult muscle differentiation through two broad and complementary aims.
In Aim 1, we shall identify the mechanism by which MEF2 functions in mediating adult muscle formation, including the factors which act alongside MEF2 in adult myogenesis. This will be achieved by determining the ability of MEF2 mutants to rescue adult and embryonic muscle development, by identifying regions of MEF2 that have tissue-specific functions, and by carrying out a genetic enhancer screen to identify loci whose haploinsufficiency exacerbates Mef2 hypomorphs.
In Aim 2, we shall identify and characterize the regulatory factors responsible for the expression of adult muscle structural genes, via analyses of adult muscle-specific enhancers that we have identified, and by utilizing a new RNAi-based screen to identify genes which are required for the activity of adult muscle enhancers. The overall results of our experiments will provide a comprehensive view of how the complex muscles of the Drosophila adult are built. Given the strong evolutionary conservation in developmental regulatory processes between Drosophila and mammals, our studies will provide basic molecular mechanisms for how distinct skeletal muscle types differentiate and acquire fiber-specific properties. The developmental regulatory networks that we define in the Drosophila system will be an essential framework upon which to build our understanding of mammalian muscle development, disease, and repair.

Public Health Relevance

Human muscles contain multiple fiber types, yet there is still much to learn in defining how these fiber types arise and how their fate is controlled. Moreover, a number of human muscle diseases preferentially affect one class of muscles over another. By defining mechanisms for how individual muscle arises in the body, our studies will provide a deeper understanding of how some muscles might be more sensitive to the development of pathologies, and how the symptoms of such diseases might be ameliorated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061738-12
Application #
8392279
Study Section
Special Emphasis Panel (ZRG1-MOSS-R (02))
Program Officer
Hoodbhoy, Tanya
Project Start
2001-05-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
12
Fiscal Year
2013
Total Cost
$291,430
Indirect Cost
$98,430
Name
University of New Mexico
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Oas, Sandy T; Bryantsev, Anton L; Cripps, Richard M (2014) Arrest is a regulator of fiber-specific alternative splicing in the indirect flight muscles of Drosophila. J Cell Biol 206:895-908
Chechenova, Maria B; Bryantsev, Anton L; Cripps, Richard M (2013) The Drosophila Z-disc protein Z(210) is an adult muscle isoform of Zasp52, which is required for normal myofibril organization in indirect flight muscles. J Biol Chem 288:3718-26
Morriss, Ginny R; Jaramillo, Carmelita T; Mikolajczak, Crystal M et al. (2013) The Drosophila wings apart gene anchors a novel, evolutionarily conserved pathway of neuromuscular development. Genetics 195:927-40
Bryantsev, Anton L; Baker, Phillip W; Lovato, TyAnna L et al. (2012) Differential requirements for Myocyte Enhancer Factor-2 during adult myogenesis in Drosophila. Dev Biol 361:191-207
Bryantsev, Anton L; Cripps, Richard M (2009) Cardiac gene regulatory networks in Drosophila. Biochim Biophys Acta 1789:343-53
Jaramillo, Maryann S; Lovato, Candice V; Baca, Erica M et al. (2009) Crossveinless and the TGFbeta pathway regulate fiber number in the Drosophila adult jump muscle. Development 136:1105-13
Lovato, TyAnna L; Adams, Melanie M; Baker, Phillip W et al. (2009) A molecular mechanism of temperature sensitivity for mutations affecting the Drosophila muscle regulator Myocyte enhancer factor-2. Genetics 183:107-17
Tanaka, Kathleen K Kelly; Bryantsev, Anton L; Cripps, Richard M (2008) Myocyte enhancer factor 2 and chorion factor 2 collaborate in activation of the myogenic program in Drosophila. Mol Cell Biol 28:1616-29
Denmark, Scott E; Baird, John D (2006) Palladium-catalyzed cross-coupling reactions of heterocyclic silanolates with substituted aryl iodides and bromides. Org Lett 8:793-5
Baker, Phillip W; Tanaka, Kathleen K Kelly; Klitgord, Niels et al. (2005) Adult myogenesis in Drosophila melanogaster can proceed independently of myocyte enhancer factor-2. Genetics 170:1747-59

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