Figure 1. Three universal stages in the cell fusion pathway
(Stage I) Specification of the fusion fate
(Stage II) Cell attraction, attachment and recognition
(Stage III) Execution of cell membrane and cytoplasmic fusion (a model)
Cell fusion is essential for sexual reproduction since fertilization requires the fusion of male and female gametes . In addition, somatic cells fuse to sculpt organs such as in muscles, bones, placenta, eye lens and other organs throughout the animal kingdom . However, little is known regarding the molecular mechanisms of cell fusion despite extensive attempts and a few notable exceptions . Caenorhabditis elegans is a remarkable organism to study cell-cell fusion because more than one third of all the somatic cells and all the germ cells invariantly fuse during normal development in the skin, pharyngeal muscles, reproductive system, digestive system, excretory systems and nervous system. We have identified the first family of cellular fusion proteins (fusogens EFF-1 and AFF-1 in C. elegans) [3,4]. The current focus is determining the pattern and process by which cellular fusogens fuse eukaryotic cells during development.
EFF-1 (Epithelial Fusion Failure-1) and AFF-1 (Anchor cell Fusion Failure-1) are type I membrane proteins necessary and sufficient for cell fusion: eliminating fusion when absent and fusing cells when ectopically expressed on the membranes of the nematode C. elegans and heterologous cells [4,5]. We have shown that EFF-1 and AFF-1 must be expressed in both fusing cells, and thus that they act via novel homotypic interactions . The fusion process shares a hemifusion intermediate with viral and intracellular membrane fusion processes (Fig. 1).
Homologs of EFF-1 and AFF-1 are present in over forty different nematode species , six arthropods, two ctenophores and one chordate. We hypothesize that diverse cell fusion events in nature will follow similar mechanisms as FF-mediated fusion. We will find the missing fusogens across kingdoms. Our evidence of the intermediates of the fusion process mediated by EFF-1 and AFF-1 in vitro and in vivo suggests that FF proteins fuse membranes by a mechanism analogous to viral fusogens or by a novel fusogenic paradigm . Thus one present goal is to discover the mechanism of FF-mediated cell fusion.
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