Nodal Antagonists in the Anterior Visceral Endoderm Prevent the Formation of Multiple Primitive Streaks

Abstract

The anterior visceral endoderm plays a pivotal role in establishing anterior-posterior polarity of the mouse embryo, but the molecular nature of the signals required remains to be determined. Here, we demonstrate that Cerberus-like(-/-);Lefty1(-/-) compound mutants can develop a primitive streak ectopically in the embryo. This defect is not rescued in chimeras containing wild-type embryonic, and Cerberus-like(-/-);Lefty1(-/-) extraembryonic, cells but is rescued in Cerberus-like(-/-); Lefty1(-/-) embryos after removal of one copy of the Nodal gene. Our findings provide support for a model whereby Cerberus-like and Lefty1 in the anterior visceral endoderm restrict primitive streak formation to the posterior end of mouse embryos by antagonizing Nodal signaling. Both antagonists are also required for proper patterning of the primitive streak.

The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice

“…Similar to Lrp5 +/-;Lrp6 -/-embryos, an expansion of anterior primitive streak derivatives coupled with a loss of trunk mesoderm is observed in some classes of Cer1 -/-;Leftb -/-mutants and in Drap1 mutants (Perea-Gomez et al, 2002;Iratni et al, 2002). As Cer1 and Leftb are Nodal antagonists, and Drap1 is probably a transcriptional corepressor for Nodal, these defects appear to be a consequence of increased levels of Nodal signaling.…”

“…Together, these results demonstrate that derivatives of the anterior primitive streak, in particular the ADE, are expanded in Lrp5 +/-;Lrp6 -/-embryos. An expansion of anterior primitive streak derivatives is observed in some classes of Cer1 -/-;Leftb -/-mutants and in Drap1 mutants (Perea-Gomez et al, 2002;Iratni et al, 2002). Moreover, both these mutants fail to specify paraxial mesoderm and Drap1 mutants produce an excess of mesodermal cells at the primitive streak.…”

Nucleotide exchange factor RIC‐8 is indispensable in mammalian early development

“…AVE is crucial for the correct anterior-posterior pattering and is functioning as a source of antagonists (CER-1, LEFTY-1) for posteriorizing signals (NODAL, WNT-3) and the correct positioning of the primitive streak (Brennan et al, 2001;Srinivas, 2006). Embryos lacking LEFTY-1 and CER-1 function possess severe patterning defects, including occasional duplications of the primitive streak (Perea-Gomez et al, 2002). The expression pattern of Cer-1 in the anterior region of Ric-8 þ/þ and Ric-8 À/À mutant embryos (n ¼ 3) was almost indistinguishable at the onset of gastrulation at E6.5 ( Fig.…”

21st Century neontology and the comparative development of the vertebrate skull

“…These studies further serve to highlight the idea that the appropriate balance of NO-derivative cell fates (endoderm, mesoderm, and mesendoderm) must be achieved. Balanced Nodal signaling must be achieved in such a manner that the "anterior" ectoderm already in placeboth presumptive neurectoderm and cephalic surface ectoderm-is protected (by Nodal antagonists such as Cerberus and Lefty) from a signaling cascade that converts ectoderm into endoderm and mesoderm (Piccolo et al, 1999;Niehrs, 1999;Thisse et al, 2000;Perea-Gomez et al, 2002;Yamamoto et al, 2004;Kuroda et al, 2004). Protection of the anterior ectoderm appears to be one function of the NO-derived AME (Glinka et al, 1997(Glinka et al, , 1998Shimamiura and Rubenstein, 1997;Bachillier et al, 2000;de Souza and Niehrs, 2000;Kazanskaya et al, 2000;Kiecker and Niehrs, 2001;Mukhopadhyay et al, 2001;Anderson et al, 2002;del Barco Barrantes et al, 2003).…”