258
Despite this requirement for anterior development, several experiments have
revealed that the hypoblast and related tissues largely lack head organizing proper-
ties. Einsteck implantation of the prospective foregut endoderm in Xenopus fails to
result in ectopic head induction (Bouwmeester et al. 1996 ). Similar results were
seen in chick and mouse regarding the function of the AVE/hypoblast, which like-
wise fail to induce anterior structures in transplant assays (Tam and Steiner 1999 ;
Foley et al. 2000 ). Additionally, removal of the hypoblast/AVE results in ectopic
primitive streak and mesoderm formation and anteriorization of the embryo, dem-
onstrating that these tissues are repressors rather than inducers of mesoderm
(Bertocchini and Stern 2002 ) as well as permissive regulators of anterior development
(Yamamoto et al. 2004 ). Thus a more complex picture of anteroposterior patterning
is emerging in which the hypoblast/AVE/anterior endoderm self-organizes its own
morphogenesis and engages in reciprocal signaling with the epiblast/prospective
definitive mesendoderm to control cell fate and morphogenesis in the embryo.
6.5.1.2 Formation and Migration of the Hypoblast/AVE
The initial formation of the hypoblast/AVE has been studied with considerable
detail in the mouse but is little understood in the chicken. In the latter case, hypo-
blast cells delaminate from the early epiblast, forming isolated clusters, which
merge together from posterior-to-anterior (Stern 2004 ). While it has never been
studied as such, it is likely that this process is analogous to the cell sorting of primi-
tive endoderm from epiblast in the mouse blastocyst. In the mouse, the primitive
endoderm in contact with the epiblast (embryonic visceral endoderm) differentiates
into the visceral endoderm after implantation, under the control of BMP signaling
(Yamamoto et al. 2009 ). Continuing BMP signals from the epiblast and extraembry-
onic ectoderm likely inhibit the formation of the AVE at the proximal end of the
mouse egg cylinder (Rodriguez 2005 ; Mesnard et al. 2006 ). The AVE is ultimately
specified through the activation of Nodal/Smad2 signals from the epiblast (Waldrip
et al. 1998 ; Brennan et al. 2001 ) and the inhibition of BMP/Smad1 signals
(Yamamoto et al. 2009 ).
In the presumptive AVE, Nodal indirectly and directly induces a number of AVE
transcription factors as well as the expression of Nodal antagonists Lefty1 and
Cerberus-like (Cerl) and the Wnt antagonists Dickkopf1 and Sfrp5 (Brennan et al.
2001 , see below). The expression of Lefty1 and Cerl in the AVE inhibits the autoregu-
latory maintenance of Nodal expression in the distal epiblast (Norris et al. 2002 ). As
AVE migration commences and is replaced by posterior visceral endoderm, Nodal and
Nodal target gene expression are gradually restricted to the posterior epiblast, mediat-
ing mesoderm induction and primitive steak formation (Ding et al. 1998 ; Brennan
et al. 2001 ; Perea-Gomez et al. 2002 ; Yamamoto et al. 2004 ). Thus, anterior migration
of the AVE has several consequences for anteroposterior patterning: the maintenance
of ectoderm germ layer and anterior neural in the anterior epiblast, and the removal of
inhibitory signals for primitive streak/mesendoderm formation (Fig. 6.13).
D.W. Houston