Getting there in one piece: The Rac pathway prevents cell fragmentation in a nonprotrusively migrating leader cell during organogenesis
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Abstract
The C. elegans hermaphrodite distal tip cell (DTC) leads gonadogenesis. Loss-of-function mutations in a C. elegans ortholog of the Rac1 GTPase ( ced-10 ) and its GEF complex ( ced-5 /DOCK180, ced-2 /CrkII, ced-12 /ELMO) cause gonad migration defects related to directional sensing; we discovered an additional defect class of gonad bifurcation in these mutants. Using genetic approaches, tissue-specific and whole-body RNAi, and in vivo imaging of endogenously tagged proteins and marked cells, we find that loss of Rac1 or its regulators causes the DTC to fragment as it migrates. Both products of fragmentation—the now-smaller DTC and the membranous patch of cellular material—localize important stem cell niche signaling (LAG-2/DSL ligand) and migration (INA-1/integrin subunit alpha) factors to their membranes, but only one retains the DTC nucleus and therefore the ability to maintain gene expression over time. The enucleate patch can lead a bifurcating branch off the gonad arm that grows through germ cell proliferation. Germ cells in this branch differentiate as the patch loses LAG-2 expression. While the nucleus is surprisingly dispensable for aspects of leader cell function, it is required for stem cell niche activity long-term. Prior work found that Rac1 −/− ;Rac2 −/− mouse erythrocytes fragment; in this context, our new findings support the conclusion that maintaining a cohesive but deformable cell is a conserved function of this important cytoskeletal regulator.
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to continue to produce LAG-2 protein
in future work it would be really cool to use the auxin system to have a means of rapidly degrading LAG-2 protein in both niches (assuming that TIR1 gets inherited into the patch of. course) - but if it does, it would give you a way of functionally testing the temporal aspect - if you degrade the LAG-2 early vs late...
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coexpressing
if it's helpful to point out, the lag-2 bmb202 allele is an endogenous read-out of lag-2 transcription since it's knocked in at the lag-2 locus.
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Figure 2
i love this figure! Since your RNAi and mutants cause a range of phenotypes, it would be useful to put the penetrance for the representative image in the corner of the figure (e.g., x/y, %). You could also do this in any other figure with images showing a phenotype.
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a distal tip cell membrane marker
just to help with clarity, mention that it's an mNG marker here, so when you bring up mNG below the connection is immediately obvious
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