View Program - 63rd Annual Drosophila Research Conference

Cell-cell fusion is a fundamental process in the development of multicellular organisms, where it is involved in diverse processes such as fertilization, myogenesis, bone resorption and placenta formation. Drosophila embryonic musculature is an excellent genetically tractable model to study cell-cell fusion, as it results from the fusion between two types of cells – muscle founder cells and fusion competent myoblasts (FCMs). Previous studies in our lab have identified many molecular components in myoblast fusion and revealed an asymmetric “fusogenic synapse”, wherein the FCM generates an actin-enriched podosome-like structure (PLS) to invade the founder cell to promote cell membrane fusion.
We previously identified an Arf GTPase guanine nucleotide exchange factor (ArfGEF), Loner, as an essential regulator of myoblast fusion. However, its precise molecular mechanism of action remains poorly understood. We found that actin-enriched PLS form at the fusogenic synapse between founder cells and FCMs in loner mutant embryos. However, time-lapse imaging data suggest that they are more diffused and unstable than the control embryos, failing to invade the founder cells properly to induce cell fusion. Our genetic rescue experiments showed that while Loner in required in both founder cells and FCMs, it plays a major role in the FCMs. Consistent with this, Loner is recruited to the fusogenic synapse in the FCMs but not the founder cells. Our structure-function analysis of Loner show that multiple domains of Loner can interact with FCM-specific cell adhesion molecule Sns, suggesting that Loner may be recruited to the fusogenic synapse by Sns. Thus, we hypothesize that Loner promotes actin nucleation promoting factors at the fusogenic synapse of FCMs. Currently, we are investigating how Loner and its downstream Arf GTPases interact and regulate the actin nucleation promoting factors.

Understanding the Role of Loner in Myoblast Fusion.