Myoblast fusion: When it takes more to make one

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 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 are 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.     

Endocytic trafficking of Wingless and its receptors, Arrow and DFrizzled-2, in the Drosophila wing

During animal development, Wnt/Wingless (Wg) signaling is required for the patterning of multiple tissues. While insufficient signal transduction is detrimental to normal development, ectopic activation of the pathway can be just as devastating. Thus, numerous controls exist to precisely regulate Wg signaling levels. Endocytic trafficking of pathway components has recently been proposed as one such control mechanism. Here, we characterize the vesicular trafficking of Wg and its receptors, Arrow and DFrizzled-2 (DFz2), and investigate whether trafficking is important to regulate Wg signaling during dorsoventral patterning of the larval wing. We demonstrate a role for Arrow and DFz2 in Wg internalization. Subsequently, Wg, Arrow and DFz2 are trafficked through the endocytic pathway to the lysosome, where they are degraded in a hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner. Surprisingly, we find that Wg signaling is not attenuated by lysosomal targeting in the wing disc. Rather, we suggest that signaling is dampened intracellularly at an earlier trafficking step. This is in contrast to patterning of the embryonic epidermis, where lysosomal targeting is required to restrict the range of Wg signaling. Thus, signal modulation by endocytic routing will depend on the tissue to be patterned and the goals during that patterning event.     

Expression and functional analysis of a novel Fusion Competent Myoblast specific GAL4 driver

In the Drosophila embryo, body wall muscles are formed by the fusion of two cell types, Founder Cells (FCs) and Fusion Competent Myoblasts (FCMs). Using an enhancer derived from the Dmef2 gene ([C/D]( *)), we report the first GAL4 driver specifically expressed in FCMs. We have determined that this GAL4 driver causes expression in a subset of FCMs and, upon fusion, in developing myotubes from stage 14 onwards. In addition, we have shown that using this Dmef2-5x[C/D]( *)-GAL4 driver to express dominant negative Rac in only FCMs causes a partial fusion block. This novel GAL4 driver will provide a useful reagent to study Drosophila myoblast fusion and muscle differentiation.     

Polymerizing Microtubules Activate Site-directed F-Actin Assembly in Nerve Growth Cones

We identify an actin-based protrusive structure in growth cones termed "intrapodium." Unlike filopodia, intrapodia are initiated exclusively within lamellipodia and elongate in a continuous (nonsaltatory) manner parallel to the plane of the dorsal plasma membrane causing a ridge-like protrusion. Intrapodia resemble the actin-rich structures induced by intracellular pathogens (e.g., Listeria) or by extracellular beads. Cytochalasin B inhibits intrapodial elongation and removal of cytochalasin B produced a burst of intrapodial activity. Electron microscopic studies revealed that lamellipodial intrapodia contain both short and long actin filaments oriented with their barbed ends toward the membrane surface or advancing end. Our data suggest an interaction between microtubule endings and intrapodia formation. Disruption of microtubules by acute nocodazole treatment decreased intrapodia frequency, and washout of nocodazole or addition of the microtubule-stabilizing drug Taxol caused a burst of intrapodia formation. Furthermore, individual microtubule ends were found near intrapodia initiation sites. Thus, microtubule ends or associated structures may regulate these actin-dependent structures. We propose that intrapodia are the consequence of an early step in a cascade of events that leads to the development of F-actin-associated plasma membrane specializations.     

Predictive mapping of human risk for West Nile virus (WNV) based on environmental and socioeconomic factors

A West Nile virus (WNV) human risk map was developed for Suffolk County, New York utilizing a case-control approach to explore the association between the risk of vector-borne WNV and habitat, landscape, virus activity, and socioeconomic variables derived from publically available datasets. Results of logistic regression modeling for the time period between 2000 and 2004 revealed that higher proportion of population with college education, increased habitat fragmentation, and proximity to WNV positive mosquito pools were strongly associated with WNV human risk. Similar to previous investigations from north-central US, this study identified middle class suburban neighborhoods as the areas with the highest WNV human risk. These results contrast with similar studies from the southern and western US, where the highest WNV risk was associated with low income areas. This discrepancy may be due to regional differences in vector ecology, urban environment, or human behavior. Geographic Information Systems (GIS) analytical tools were used to integrate the risk factors in the 2000-2004 logistic regression model generating WNV human risk map. In 2005-2010, 41 out of 46 (89%) of WNV human cases occurred either inside of (30 cases) or in close proximity (11 cases) to the WNV high risk areas predicted by the 2000-2004 model. The novel approach employed by this study may be implemented by other municipal, local, or state public health agencies to improve geographic risk estimates for vector-borne diseases based on a small number of acute human cases.     

The rise of the invasives and decline of the natives: insights revealed from adult populations of container-inhabiting Aedes mosquitoes (Diptera: Culicidae) in temperate North America

Container-inhabiting Aedes mosquitoes are successful invaders and important arthropod-borne disease vectors worldwide. In North America, a subtropical assemblage containing introduced Aedes albopictus and Aedes aegypti and the native Aedes triseriatus have served as a model for investigating ecological interactions during invasions and focused on the outcomes at the larval stages. We report a hypothesis driven study of a more temperate container Aedes assemblage at the adult population level monitored in the state of New Jersey during a 9-year period. The invasive A. albopictus and Aedes japonicus abundances increased by a factor of two, whereas A. triseriatus abundance decreased by a factor of three. Spatiotemporal analysis indicated these trends were coincident especially in the areas invaded by A. albopictus, leading to partial displacement of A. triseriatus. Although the invasive species reached peak abundance in highly urbanized areas, the native species’ rate of decline was similar across the urbanization gradient. Higher winter temperatures and precipitation favored increased A. albopictus abundance suppressing A. triseriatus adult populations in turn, whereas A. japonicus abundance was promoted by summer precipitation. The results validate the conceptual framework developed for subtropical container Aedes and suggest that the current climatic trends will favor further spread of A. albopictus, amplifying public health concerns.     

Climate Change and Range Expansion of the Asian Tiger Mosquito (Aedes albopictus) in Northeastern USA: Implications for Public Health Practitioners

The Asian tiger mosquito, Aedes albopictus (Skuse), is an invasive species with substantial biting activity, high disease vector potential, and a global distribution that continues to expand. New Jersey, southern New York, and Pennsylvania are currently the northernmost boundary of established Ae. albopictus populations in the eastern United States. Using positive geographic locations from these areas, we modeled the potential future range expansion of Ae. albopictus in northeastern USA under two climate change scenarios. The land area with environmental conditions suitable for Ae. albopictus populations is expected to increase from the current 5% to 16% in the next two decades and to 43%–49% by the end of the century. Presently, about one-third of the total human population of 55 million in northeastern USA reside in urban areas where Ae. albopictus is present. This number is predicted to double to about 60% by the end of the century, encompassing all major urban centers and placing over 30 million people under the threat of dense Ae. albopictus infestations. This mosquito species presents unique challenges to public health agencies and has already strained the resources available to mosquito control programs within its current range. As it continues to expand into areas with fewer resources and limited organized mosquito control, these challenges will be further exacerbated. Anticipating areas of potential establishment, while planning ahead and gathering sufficient resources will be the key for successful public health campaigns. A broad effort in community sanitation and education at all levels of government and the private sector will be required until new control techniques are developed that can be applied efficiently and effectively at reasonable cost to very large areas.