Academic journal article Genetics

A Cis-Regulatory Mutation in Troponin-I of Drosophila Reveals the Importance of Proper Stoichiometry of Structural Proteins during Muscle Assembly

Academic journal article Genetics

A Cis-Regulatory Mutation in Troponin-I of Drosophila Reveals the Importance of Proper Stoichiometry of Structural Proteins during Muscle Assembly

Article excerpt

THE indirect fl ight muscles (IFMs) of Drosophila serve as a good genetic model system to study muscle development, assembly of structural proteins, and regulation of muscle contraction (Vigoreaux 2006; Nongthomba et al. 2007). Like the vertebrate skeletal muscles, IFM contraction is regulated by the influx of neurally stimulated intracellular Ca2+. Stretch activation allows IFM to contract at a much higher frequency and is similar to the asynchronous muscle contraction in the human heart (Peckham et al. 1990; Josephson et al. 2000; Agianian et al. 2004; Moore et al. 2006). In addition, major structural proteins like myosin, actin, tropomyosin (Tm), troponin (Tn), a-actinin, etc., that are involved in the assembly of sarcomeres, are conserved in vertebrates and invertebrates and dispense similar functions. Mutations in these sarcomeric proteins disrupt muscle structure and function (summarized in Vigoreaux 2006). Since IFMs are the only fibrillar muscles present in a fly's body, many of the myofibrillar proteins have IFM-specific isoforms (Cripps 2006; Nongthomba et al. 2007) and are dispensable under laboratory conditions, enabling the isolation of mutations without affecting other physiological activities. The majority of mutations affecting the IFMs were isolated during mutagenesis screens for flightless behavior (Deak 1977; Homyk and Sheppard 1977; Mogami and Hotta 1981; Deak et al. 1982; Cripps et al. 1994; summarized in Cripps 2006). However, molecular lesions for many of these mutations are yet to be identified; as a result, plausible mechanisms that give rise to muscle phenotype of these mutations remain elusive.

Many of these flightless mutants are known to show a muscle phenotype that has been categorized as "hypercontraction." Hypercontraction is a phenomenon that leads to muscle defects like thinning and tearing, following uncontrolled actomyosin interactions of otherwise normally assembled sarcomeric structures (Nongthomba et al. 2003). Mutations leading to hypercontraction have been localized in structural genes such as the upheld gene (up101) (Fyrberg et al. 1990; Nongthomba et al. 2003), flightin (fln0) (Reedy et al. 2000), Actin88F (An and Mogami 1996; Nongthomba et al. 2003), Myosin heavy chain (Mhc6, Mhc13, and Mhc19) (Kronert et al. 1995), wings up A (wupAhdp-2) (Beall and Fyrberg 1991; Nongthomba et al. 2003), the protein phosphatase genes flapwing (flw1, flw6, and flw7) (Raghavan et al. 2000; Pronovost et al. 2013), and calcineurin B2 (canB2EP(2)0774) (Gajewski et al. 2006). Mutations producing hypercontraction fall in a large repertoire of proteins, suggesting that there could be multiple grounds for reaching the phenotype. Suppressor studies of the hypercontraction phenotype have led to the identification of mutations in structural genes like Tm2 (Naimi et al. 2001), Mhc (Kronert et al. 1999; Nongthomba et al. 2003), and the integrin adhesive complex protein PINCH (Pronovost et al. 2013), providing very fruitful insights into the structure-function relationship of these proteins. Studies of these hypercontracting alleles have led to the conclusion that defects in Ca2+ regulation, structural defects, troponin-tropomyosin (Tn-Tm) regulation defects, and mechanical stress can lead to IFM hypercontraction (Nongthomba et al. 2003; Cammarato et al. 2004; Pronovost et al. 2013). However, further work is required to identify genes/proteins and pathways involved in the pathogenesis of hypercontraction to unravel new players involved in the regulation of muscle contraction and possible mechanisms leading to muscle dysfunction, as is the case with most human myopathies.

Detailed characterization of the flightless mutations, which were isolated decades ago, has led to the identification of many proteins and residues that are important for muscle assembly, function and diseases (reviewed in Cripps 2006; Vigoreaux 2006). Previously, we have shown detailed characterization of the mutation up1, which was isolated in 1958 (Fahmy and Fahmy 1958) and which yielded new insights into troponin-T (TnT) isoform switching, muscle assembly, and function (Nongthomba et al. …

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