Somatic muscle formation is an unusual process as it requires the cells involved, the myoblasts, to relinquish their individual state and fuse with one another to form a syncitial muscle fiber. The potential use of myoblast fusion therapies to rebuild damaged muscles has generated continuing interest in elucidating the molecular basis of the fusion process. Yet, until recently, few of the molecular players involved in this process had been identified. Now, however, it has been possible to couple a detailed (...) understanding of the cellular basis of the fusion process with powerful classical and molecular genetic strategies in the Drosophila embryo. We review the cellular studies, and the recent genetic and biochemical analyses that uncovered interacting extracellular molecules present on fusing myoblasts and the intracellular effectors that facilitate fusion. With the conservation of proteins and protein functions across species, it is likely that these findings in Drosophila will benefit understanding of the myoblast fusion process in higher organisms. BioEssays 24:591–601, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Over several years, genetic studies in the model system, Drosophila melanogastor, have uncovered genes that when mutated, lead to a block in myoblast fusion. Analyses of these gene products have suggested that Arp2/3‐mediated regulation of the actin cytoskeleton is crucial to myoblast fusion in the fly. Recent advances in imaging in Drosophila embryos, both in fixed and live preparations, have led to a new appreciation of both the three‐dimensional organization of the somatic mesoderm and the cell biology underlying (...) myoblast fusion. BioEssays 30:423–431, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Skeletal myoblasts have their origin early in embryogenesis within specific somites. Determined myoblasts are committed to a myogenic fate; however, they only differentiate and express a muscle‐specific phenotype after they have received the appropriate environmental signals. Once proliferating myoblasts enter the differentiation programme they withdraw from the cell cycle and form post‐mitotic multinucleated myofibres (myogenesis); this transformation is accompanied by muscle‐specific gene expression. Muscle development is associated with complex and diverse protein isoform transitions, generated by differential gene expression and mRNA (...) splicing. The myofibres are in a state of dynamic adaptation in response to hormones, mechanical activity and motor innervation, which modulate differential gene expression and splicing during this functional acclimatisation. This review will focus on the profound effects of thyroid hormone on skeletal muscle, which produce alterations in gene and isoform expression, biochemical properties and morphological features that precipitate in modified contractile/mechanical characteristics. Insight into the molecular events that control these events was provided by the recent characterisation of the MyoD gene family, which encodes helix‐loop‐helix proteins; these activate muscle‐specific transcription and serve as targets for a variety of physiological stimuli. The current hypothesis on hormonal regulation of myogenesis is that thyroid hormones (1) directly regulate the myoD and contractile protein gene families, and (2) induce thyroid hormone receptor‐transcription factor interactions critical to gene expression. (shrink)

Gene targeting has allowed the dissection of complex biological processes at the genetic level. Our understanding of the nuances of skeletal muscle development has been greatly increased by the analysis of mice carrying targeted null mutations in the Myf‐5, MyoD and myogenin genes, encoding members of the myogenic regulatory factor (MRF) family. These experiments have elucidated the hierarchical relationships existing between the MRFs, and established that functional redundancy is a feature of the MRF regulatory network. Either MyoD or Myf‐5 is (...) sufficient for the formation or survival of skeletal myoblasts. Myogenin acts later in development and plays an essential in vivo role in the terminal differentiation of myotubes. (shrink)

Mammalian sperm undergo discharge of a single, anterior secretory granule following their attachment to the zona pellucida surrounding the oocyte. This secretory discharge is known for historical reasons as the acrosome reaction. It fulfils a number of purposes and without it, sperm are unable to penetrate the zona pellucida and fuse with the oocyte. In this review, we focus on the role of the acrosome reaction in the development of fusion competence in sperm. Any naturally occurring membrane fusion has two (...) major sequential steps: a docking or adhesion step, in which two membranes adhere, and a fusion step, in which their lipid bilayers are destabilized and merged and a cellular compartment is either created or destroyed. Recent evidence suggests that there is an important role for oocyte integrins and sperm‐bound disintegrins in mammalian sperm/oocyte adhesion and fusion. The fusion mechanism employed by sperm remains poorly understood, however, and circumstantial evidence suggests it is more complex than the interaction between a single protein species and its target. Sperm/oocyte fusion is probably the most accessible eukaryotic model for intercellular fusion currently available, partly because it is temporally separated from gene expression. Elucidation of the mechanism of sperm/oocyte fusion may throw light on the mechanism of other intercellular fusions such as myoblast fusion, and the evolutionary relationship of intercellular membrane fusion to intracellular membrane fusion. (shrink)

Skeletal muscle formation is studied in vitro with myogenic cell lines and primary muscle cell cultures, and in vivo with embryos of several species. We review several of the notable advances obtained from studies of cultured cells, including the recognition of myoblast diversity, isolation of the MyoD family of muscle regulatory factors, and identification of promoter elements required for muscle‐specific gene expression. These studies have led to the ideas that myoblast diversity underlies the formation of the multiple types (...) of fast and slow muscle fibers, and that myogenesis is controlled by a combination of ubiquitous and muscle‐specific transcriptional regulators that may be different for each gene. We further review some unexpected results that have been obtained when ideas from work in culture have been tested in developing animals. The studies in vivo point to additional molecular and cellular mechanisms that regulate muscle formation in the animal. (shrink)

The mechanism(s) by which the thymidine analogue 5‐bromodeoxyuridine (BUdR) specifically inhibits the expression of differentiated functions is poorly understood, as are the ways in which cells regulate processes exhibiting probabilistic aspects. I have developed a theoretical model for the regulation of the decision of myogenic cells to differentiate that can explain both of the above phenomena. This model provided a strategy for isolating myoblast variants that had amplified the expression of the factors regulating the decision to differentiate. These myoblasts (...) served as the source of mRNA for making and screening a cDNA library in order to isolate these factors. The successful cloning of these genes should represent a major advance in our understanding of the molecular basis for the major coordinated changes in gene expression that accompany cell differentiation. (shrink)

As life extended into eukaryota, a great host of strategies emerged in the pursuit of cellular life. Some cells have been successful in solitude, some moved into cooperatives (i.e., multicellular organisms), but one additional strategy emerged. Throughout eukaryotes, many of the diverse multicellular cooperatives took life in partnership one step further. These cells came together and lost their singularity in the expanse of syncytial life. Recently in our search for this elusive “how”, we discovered the intriguing peculiarity of a nuclear, (...) RNA‐binding protein living a second life as a fusion manager at the surface of developing osteoclasts, ushering them into syncytia 1. It is from here that we will develop several thoughts about the advantages of multinucleated cells and discuss how these fusing cells pass through several hallmarks of cell death. We will propose that cell fusion shares much with cell death because cell fusion is a death of sorts for the cells that undergo it – a death of the life that was and the beginning of new life in a community without borders. (shrink)