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Lefty1-expressing primary AVE arises asymmetrically within the primitive endo-
derm (E4.0–5.0; Takaoka et al. 2006 ; Torres-Padilla et al. 2007b), with live imaging
of cultured embryos revealing a second population gaining Cerl-expression at E5.0
(Torres-Padilla et al. 2007b). Genetic lineage labeling of Lefty1-expressing cells
confirmed that the secondary AVE arises from progenitors that lack early Lefty1-
expression (Takaoka et al. 2011 ).
The leading role of the primary AVE was suggested through microsurgical
ablation of the primary AVE, which resulted in a wider defect in remaining VE
migration (Miura and Mishina 2007 ). Importantly, inducible genetic lineage
ablation of Lefty1-expressing cells clearly showed that the secondary AVE does
not migrate anteriorly if early Lefty1-expressing primitive endoderm is elimi-
nated (Takaoka et al. 2011 ). Similar results were seen in live imaging of embryos
cultured on a collagen-coated polyacrylamide matrix to mimic implantation
(Morris et al. 2012a). In this case, laser ablation of leading “pioneer” cells
expressing the highest levels of Cerl prevented the migration of the
AVE. Interestingly, ablation of an immediate “follower” cell also inhibited
migration, suggesting that a coherent stream of interacting cells is necessary for
anterior migration (Morris et al. 2012a).
This behavior conceptually resembles “follow-the-leader” collective cell migra-
tion strategies evident in epithelial wound healing, lateral line and neural crest cell
migration, cancer metastasis and other paradigms (Friedl and Gilmour 2009 ; Wynn
et al. 2012 ; Cheung et al. 2013 ; Dalle Nogare et al. 2014 ; Yamaguchi et al. 2015 ).
However, many of the well-characterized cases involve mesenchymal cells or
epithelial- to-mesenchymal transitions, whereas AVE migration occurs by direc-
tional intercalation and neighbor exchange within the simple epithelium of the vis-
ceral endoderm (Srinivas et al. 2004 ). Trinkaus performed seminal work on
coordinated migration in epithelial sheets and coupled protrusive behavior over 40
years ago (Vaughan and Trinkaus 1966 ), but the mechanisms controlling follow-
the- leader behavior are only beginning to be studied. Recent data in Xenopus sug-
gest that cell–cell adhesion between leaders and followers results in mechanical
stimulation of cadherins and formation of a cadherin-keratin-plakoglobin complex,
which is critical for stimulating protrusive behavior opposite the site of cell–cell
contact (Weber et al. 2012 ). This maintenance of cellular tension as well as
chemoattraction by the leading cells is likely to play key roles in this coordinated
chain migration.
The initiation of AVE migration is similarly not well understood. Nodal-
dependent cell proliferation in the epiblast is required (Stuckey et al. 2011 ), sug-
gesting that the egg cylinder may need to reach a critical size, possibly to extend the
AVE outside the reach of inhibitory signals. Thus, an initial asymmetry in the AVE,
established when the embryo is small, would be amplified during growth and would
determine the direction of subsequent migration, which is maintained by coordi-
nated cell movements.
D.W. Houston