Cell-cell fusion is a crucial and highly regulated event in the genesis of both form and function of many tissues. One particular type of cell fusion, myoblast fusion, is a key cellular process that shapes both the formation and repair of muscle. Despite its importance for human health, the mechanisms underlying this process are still not well understood. The purpose of this review is to highlight the recent literature pertaining to myoblast fusion and to focus on a comparison of these studies across several model systems, particularly the fly, zebrafish and mouse. Advances in technical analysis and imaging have allowed identification of new fusion genes and propelled further characterization of previously identified genes in each of these systems. Among the cellular steps identified as critical for myoblast fusion is migration, recognition, adhesion, membrane alignment and membrane pore formation and resolution. Importantly, striking new evidence indicates that orthologous genes govern several of these steps across these species. Taken together, comparisons across three model systems are illuminating a once elusive process, providing exciting new insights and a useful framework of genes and mechanisms.

The parathyroid glands develop with the thymus from bilateral common primordia that develop from the 3rd pharyngeal pouch endoderm in mouse embryos at about E11, each of which separates into one parathyroid gland and one thymus lobe by E13.5. Gcm2, a mouse ortholog of the Drosophila Glial Cells Missing gene, is expressed in the parathyroid-specific domains in the 3rd pouches from E9.5. The null mutation of Gcm2 causes aparathyroidism in the fetal and adult mouse and has been proposed to be a master regulator for parathyroid development. In order to study how Gcm2 functions in parathyroid development, we investigated the mechanism that causes the loss of parathyroids in Gcm2 null mutants. Analysis of the 3rd pouch-derived primordium in Gcm2-/- mutants showed the parathyroid-specific domain was present before E12.5 but underwent programmed cell death between E12 and 12.5. RNA and protein localization studies for parathyroid hormone (Pth) in wild-type embryos showed that the presumptive parathyroid domain in the parathyroid/thymus primordia started to transcribe Pth mRNA and produce PTH protein from E11.5 before the separation of parathyroid and thymus domains. However in Gcm2-/- mutants, the parathyroid-specific domain in the common primordium did not express Pth and could not maintain the expression of two other parathyroid marker genes, CasR and CCL21, although expression of these two genes was initiated. Marker gene analysis placed Gcm2 downstream of the known transcription and signaling pathways for parathyroid/thymus organogenesis. These results suggest that Gcm2 is not required for pouch patterning or to establish the parathyroid domain, but is required for differentiation and subsequent survival of parathyroid cells.

SUMMARY Sarcomeres, the fundamental contractile units of muscles, are conserved structures composed of actin thin filaments and myosin thick filaments. How sarcomeres are formed and maintained is not well understood. Here, we show that knockdown of Drosophila cofilin ( DmCFL ), an actin depolymerizing factor, disrupts both sarcomere structure and muscle function. The loss of DmCFL also results in the formation of sarcomeric protein aggregates and impairs sarcomere addition during growth. The activation of the proteasome delays muscle deterioration in our model. Furthermore, we investigate how a point mutation in CFL2 that causes nemaline myopathy (NM) in humans affects CFL function and leads to the muscle phenotypes observed in vivo . Our data provide significant insights to the role of CFLs during sarcomere formation, as well as mechanistic implications for disease progression in NM patients.

Fusion of muscle cells called myoblasts underlies the generation and maintenance of skeletal muscle throughout an animal’s life. Emerging data indicate that cell death acts as a signal to enhance these processes in mammals.

Sarcomeres, the fundamental contractile units of muscles, are conserved structures composed of actin thin filaments and myosin thick filaments. How sarcomeres are formed and maintained is not well understood. Here, we show that knockdown of Drosophila Cofilin (DmCFL), an actin depolymerizing factor, leads to the progressive disruption of sarcomere structure and muscle function in vivo. Loss of DmCFL also results in the formation of sarcomeric protein aggregates and impairs sarcomere addition during growth. Strikingly, activation of the proteasome delayed muscle deterioration in our model. Further, we investigate how a point mutation in CFL2 that causes nemaline myopathy (NM) in humans, affects CFL function and leads to the muscle phenotypes observed in vivo. Our data provide significant insights to the role of CFLs during sarcomere formation as well as mechanistic implications for disease progression in NM patients.Thick filaments interact with thin filaments, and are crosslinked at the M-line, which is composed of proteins like obscurin (Henderson et al., 2017). While many conserved sarcomeric proteins have been identified, their incorporation into and function within the sarcomere are not completely understood. Moreover, it is still unclear as to how sarcomere size is regulated and maintained during muscle homeostasis. Understanding these fundamental areas of muscle biology is crucial, as mutations in sarcomeric proteins have been implicated in several muscle diseases.

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