Abstract
During gastrulation, distinct lineage specification into three germ layers, the mesoderm, endoderm and ectoderm, occurs through an elaborate harmony between signaling molecules along the embryonic proximo-distal and anterior-posterior axes, and Nodal signaling plays a key role in the early embryonic development governing embryonic axis formation, mesoderm and endoderm specification, and left-right asymmetry determination. However, the mechanism by which Nodal expression is regulated is largely unknown. Here, we show that Meteorin regulates Nodal expression and is required for mesendoderm development. It is highly expressed in the inner cell mass of blastocysts and further in the epiblast and extra-embryonic ectoderm during gastrulation. Genetic ablation of the Meteorin gene resulted in early embryonic lethality, presumably due to impaired lineage allocation and subsequent cell accumulation. Embryoid body culture using Meteorin-null embryonic stem (ES) cells showed reduced Nodal expression and concomitant impairment of mesendoderm specification. Meteorin-null embryos displayed reduced levels of Nodal transcripts before the gastrulation stage, and impaired expression of Goosecoid, a definitive endoderm marker, during gastrulation, while the proximo-distal and anterior-posterior axes and primitive streak formation were preserved. Our results show that Meteorin is a novel regulator of Nodal transcription and is required to maintain sufficient Nodal levels for endoderm formation, thereby providing new insights in the regulation of mesendoderm allocation.
Highlights
During embryonic axis formation, lineage specification is governed by the reciprocal signaling including Wnt, Bone morphogenetic protein (BMP), and Nodal signaling pathways among epiblast, extra-embryonic ectoderm, and visceral endoderm cell populations [1,2,3,4,5,6,7,8]
We unexpectedly found that disruption of the Meteorin gene resulted in early embryonic lethality around E7.5
In situ analysis revealed that Meteorin is expressed in the inner cell mass of blastocysts even before implantation and further in the epiblast and extra-embryonic ectoderm throughout peri-gastrulation stages, suggesting that Meteorin should play a critical role in early embryonic development
Summary
During embryonic axis formation, lineage specification is governed by the reciprocal signaling including Wnt, Bone morphogenetic protein (BMP), and Nodal signaling pathways among epiblast, extra-embryonic ectoderm, and visceral endoderm cell populations [1,2,3,4,5,6,7,8]. The proximo-distal (P–D) axis in the epiblast is primarily established by Nodal signaling that activates its antagonists Lefty and Cerberus-like (Cerl) in the distal region of the visceral endoderm [9,10]. Activation of these antagonists in the distal visceral endoderm restricts Nodal target gene expression to the proximal region. The significance of embryonic axes formation is well documented in genetic studies, the mechanisms by which these embryonic axes cause the emergence of further lineage specification remain unclear
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