Vertebrate Development Maternal to Zygotic Control (Advances in Experimental Medicine and Biology)

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Recent experiments have identified considerable complexity in the control of
AVE specification and migration. Gain-of-function studies in mouse embryos
showed that Cerl/Lefty1 and Dkk1 can act as attractants for AVE migration, whereas
Nodal and Wnts can act as repellants (Yamamoto et al. 2004 ; Kimura-Yoshida et al.
2005 ). Additionally, it is also now better appreciated that the AVE is heterogeneous,
arising from an early sub-population of primitive endoderm in the preimplantation
blastocyst, in addition to a later population established from naïve distal visceral
endoderm (Takaoka et al. 2006 ). Importantly, the primary AVE cells (alias DVE, in
some literature) originate asymmetrically in the visceral endoderm and are neces-
sary to “lead” the migration of the secondary AVE in unilateral anterior migration
(Takaoka et al. 2011 ; Morris et al. 2012a). This complexity of the AVE was first
hinted at in mice mutant for the Nodal coreceptor Tdgf1, which fail to express early
AVE markers (Ding et al. 1998 ). Although these do become expressed later, the
AVE nevertheless fails to migrate. Reporter gene analyses showed that the Cerl and

epiblast

Lefty; Cerl
Gata6 +

Lefty; Cerl

Dkk1

PE/VE

ParE

ExE

Lefty; Cerl

Hex

abc

~ E5.0 ~ E5.25 ~ E5.5

1 ̊ AVE induction

and migration

2 ̊ AVE induction

and migration

ectoderm and

anterior neural future primitive

streak

Nodal

Nodal

Wnt3

Bmp4

Nodal

Nodal; Tdgf1

Nodal; Tdgf1

Nodal

Bmp4

Bmp4

Fig. 6.13 Model for origin and role of the AVE in anteroposterior pattering in the mouse. (a) In
the peri-implantation blastocyst (E5.0), a subpopulation of primitive endoderm (PE) expressing
Lefty1 and Cerl arise stochastically positioned asymmetrically in the distal egg cylinder. This pop-
ulation requires Nodal and Tdgf1 in the epiblast and is inhibited by Bmp4 in the extraembryonic
ectoderm. (b) As the conceptus grows after implantation (E5.25), the AVE begins to also express
Wnt antagonists and is repelled by Nodal and Wnt signals; the action of BMP is limited to the
proximal epiblast and PE, allowing migration of AVE in the distal region. (c) As AVE migration
proceeds, a second set of Lefty1; Cerl-expressing cells is induced in the distal VE (2°AVE) by
Tdgf1-independent Nodal signaling. These cells and the 1°AVE migrate in a coherent stream
toward the presumptive anterior, inhibiting Nodal and Wnt signaling in the epiblast and specifying
the anterior neuroectoderm. Progressive loss of Nodal from the anterior limits activity to the pos-
terior, where Nodal and Wnt maintain and amplify each other’s expression through BMP4, induc-
ing the primitive steak (PS) in the prospective posterior. ParE parietal endoderm, PE/VE primitive/
visceral endoderm, ExE extra-embryonic ectoderm. Images were modified and adapted from:
Bedzhov I, Graham SJL, Leung CY, Zernicka-Goetz M (2014) Developmental plasticity, cell fate
specification and morphogenesis in the early mouse embryo. Philosophical Transactions of the
Royal Society B: Biological Sciences 369:20130538. doi:10.1098/rstb.2013.0538 under the terms
of the Creative Commons Attribution License CC BY 3.0

6 Vertebrate Axial Patterning: From Egg to Asymmetry