| During the course of development, a single-celled fertilized egg undergoes the remarkable process of transforming into an exquisitely patterned embryo with a mature body plan and functional organ systems. Prior to elaborating the complex tissue patterns found at mid-gestation stages, the embryo must at a very early stage establish its fundamental axes. Namely, it must distinguish the head from the tail (anterior-posterior axis), the back from the front (dorsal-ventral axis), and the left from the right (left-right axis). Members of the TGFbeta family of secreted signaling ligands have been shown to be involved in a myriad of developmental processes. One such member, Nodal, has been shown to play a role in early embryonic development. Using genetic and molecular techniques, this dissertation describes the role of the Nodal signal transduction pathway in multiple aspects of anterior-posterior patterning in early mouse embryonic development. Nodal signaling in the epiblast prior to gastrulation is responsible for global anterior-posterior patterning. Nodal mediates Smad2-independent reciprocal interactions between the epiblast and extraembryonic ectoderm by both inducing expression of posterior epiblast genes and maintaining the patterning of the extraembryonic ectoderm, thereby establishing posterior fate in the embryo. Regulation of Nodal expression in the epiblast is controlled by Wnt3 via specific enhancer elements within the Nodal locus, with complex reciprocal interactions between the epiblast and extraembryonic ectoderm upregulating Nodal expression in the proximal epiblast. Furthermore, Nodal signaling in the epiblast is responsible for patterning the visceral endoderm. In particular, Smad2 in the visceral endoderm mediates Nodal signals from the epiblast to induce the anterior visceral endoderm, which establishes anterior fate in the embryo by repressing posterior gene expression in the underlying anterior epiblast. Moreover, in addition to being required for rotation of the anterior visceral endoderm as the proximal-distal axis is converted into the anterior-posterior axis, Nodal signaling mediates a novel anterior-posterior cell sorting mechanism in the epiblast prior to gastrulation. Finally, Nodal signaling in the epiblast is required for specification of the anterior mesendoderm, which subsequently patterns the anterior neurectoderm. Thus, Nodal plays a key role in the establishment of anterior-posterior pattern in the mouse embryo. |
