1. Reviewer #3 (Public Review):

    In this manuscript, the authors use high-resolution live imaging to investigate how progenitor cells travel through an embryo to a distant site for differentiation and organ formation. The test case is the movement of dorsal forerunner cells (DFCs) in the zebrafish embryo, which give rise to a transient organ called Kupffer's vesicle that functions to establish the left-right body axis. DFCs are derived from enveloping layer (EVL) cells ~5 hours post-fertilization (hpf) and then move towards the vegetal pole of the embryo. They ultimately end up in the tailbud where they differentiate into epithelial cells to form Kupffer's vesicle between 10-11 hpf. Live imaging convincingly shows that EVL cells undergo apical constriction and delaminate from the EVL layer to form DFCs. Some DFCs remain connected to the EVL via ZO-1 enriched tight junction-like apical attachments. The authors propose that spreading of the EVL layer 'drags' the underlying DFCs towards the vegetal pole via these apical attachments. Supporting this model, EVL and DFCs co-migrate with the same speed and directionality, and perturbation of an actomyosin ring network in the yolk syncytial layer (YSL) disrupts movement of both EVL and DFCs. Between 8-9 hpf DFCs detach and are uncoupled from the EVL. The authors show that E-cadherin is necessary for DFC-DFC adhesion, and additional imaging experiments show that DFCs can extend long protrusions that 'capture' detached DFCs to facilitate clustering. Taken together, these data suggest an interesting drag mechanism for guiding progenitor cell movements, however the results presented do not fully demonstrate this mechanism, and alternative mechanisms were not thoroughly tested.

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  2. Reviewer #2 (Public Review):

    This work analyses the movement of the dorsal forerunner cells (DFCs) and its interaction with the extra-embryonic enveloping layer (EVL). By doing high-resolution time lapse microscopy the authors characterize the movement of the DFCc showing that they delaminate from the epithelium by apical constriction but they remain attached to the superficial EVL. By doing laser ablations they show that the movement of the DFCc depends on the attachment and vegetal displacement of the EVL. However, they show that with some frequencies some DFCc are detached from the rest of the cluster, leading to some random movement or even being left behind and differentiating into other cell types. Importantly, they investigate an additional mechanism to explain the movement of the DFCc detached cells. They show that single cells generate protrusions that connect them with the DFCc cluster forming an E-cadherin junction. This paper makes an important contribution by adding some new mode of migrations during development. Most of the conclusion are supported by the experiments.

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  3. Reviewer #1 (Public Review):

    Pulgar et al. describe an interesting mechanism explaining how directed motion of group of cells maintain their migratory path as a group of cells. Incomplete delamination allows here to maintain coordinated cell movements amongst the DFC. The story is self-contained, logical, well-written and just in general very nice. The mechanism described belongs to the so-called mechanical drag which is a new type of multicellular locomotion and may be a general feature involved in many morphogenetic systems.

    The major strength of the study is the extensive use of live imaging and analysis of dynamic events. The study provides a nice cellular mechanism in the process they described. The molecular mechanism would be the only weakness of the study.

    An overall very exciting study.

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  4. Evaluation Summary:

    In this study, Pulgar et al. describe an interesting phenomenon addressing organ integrity in a unique example of collective cell migration. The group focused on the migration of the dorsal forunner cells (DFC), which will constitute the left-right organizer of the zebrafish. The authors show that DFCs retain apical contacts stemming from incomplete delamination and drag detached DFCs to their final destination. The study opens a number of exciting new questions related to the mechanism underlying the 'safeguards' process and the mechanism of coordination between migration and regulation of attachment.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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