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Abstract
Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation.
Highlights
Understanding how the cellular behaviors that underlie embryonic morphogenesis are regulated is a longstanding and fundamental goal of developmental biology
We leverage results from large-scale genetic synthetic lethal screens [18] to implicate VAB-1/Eph Receptor (EphR) as an upstream activator of CDC-42 in this context. These results demonstrate the importance of CDC-42 as a key regulator of oriented cell migration and identify a genetic pathway involving highly conserved molecular components centered on CDC-42 that operates during epithelial cell intercalation
Late maternal par-6 loss of function—through par-6:: ZF1::gfp combined with zygotic loss of function, using the strong loss of function par-6 allele—resulted in similar phenotypes (33% ipsilateral comigration and 17% medial delay, n = 18) (Fig 3). These results suggest that CDC-42 and the partitioning defective (PAR) complex both act to orient and extend medial tips during dorsal intercalation
Summary
Understanding how the cellular behaviors that underlie embryonic morphogenesis are regulated is a longstanding and fundamental goal of developmental biology. Through interactions with the partitioning defective (PAR) complex [5,6,7], Cdc can regulate the microtubule cytoskeleton to reorient centrosomes in order to polarize cell division and regulate apical junctions in epithelia [8, 9]. Given these diverse and conserved molecular processes, it is reasonable to think that Cdc has roles in polarizing epithelia during intercalation
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