The Wnt Pathway Controls Cell Death Engulfment, Spindle Orientation, and Migration through CED-10/Rac

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Abstract
Wnt signalling pathways have extremely diverse functions in animals, including induction of cell fates or tumours, guidance of cell movements during gastrulation, and the induction of cell polarity. Wnt can induce polar changes in cellular morphology by a remodelling of the cytoskeleton. However, how activation of the Frizzled receptor induces cytoskeleton rearrangement is not well understood. We show, by an in depth 4-D microscopy analysis, that the Caenorhabditis elegans Wnt pathway signals to CED-10/Rac via two separate branches to regulate modulation of the cytoskeleton in different cellular situations. Apoptotic cell clearance and migration of the distal tip cell require the MOM-5/Fz receptor, GSK-3 kinase, and APC/APR-1, which activate the CED-2/5/12 branch of the engulfment machinery. MOM-5 (Frizzled) thus can function as an engulfment receptor in C. elegans. Our epistatic analyses also suggest that the two partially redundant signalling pathways defined earlier for engulfment may act in a single pathway in early embryos. By contrast, rearrangement of mitotic spindles requires the MOM-5/Fz receptor, GSK-3 kinase, and β-catenins, but not the downstream factors LIT-1/NLK or POP-1/Tcf. Taken together, our results indicate that in multiple developmental processes, CED-10/Rac can link polar signals mediated by the Wnt pathway to rearrangements of the cytoskeleton. During development, processes such as cell division, fate determination, migration, and removal of dead cells occur in a directional (i.e., polar) manner. For example, cell divisions in the early embryo often occur in a directional manner to maintain specific cell–cell interactions. Later, during organ formation, tissues may be shaped through polar cell migration. During apoptosis, a neighbouring cell engulfing a cell corpse utilizes polar positional information to deform its cytoskeleton and migrate around the corpse. Wnt pathway signalling is a common mechanism by which cells establish polarity during development, but how a single Wnt signal is translated into different outcomes in different cellular or developmental contexts is not clear. Our data on C. elegans suggest that during diverse directional events—cell engulfment, mitotic spindle movement, and cell migration—different Wnt ligands or a specific signal from a cell corpse signals to the Wnt receptor Frizzled (MOM-5 in C. elegans) and on to the downstream factors CED-10/Rac. But specificity of the Wnt signal is mediated by the use of distinct intermediate signal transduction pathways. Our discovery that this pathway is also used for engulfment of cell corpses led us to propose that the two parallel pathways, originally described for engulfment of corpses, are indeed parts of one pathway involving Wnt pathway components.