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The formation of vertebrate mesoderm relies on the integration of positional information provided by several intercellular signaling pathways, including the Wnt and Bone Morphogenic Protein (Bmp) pathways. Zygotic Wnt signaling has been shown in multiple vertebrate systems to perform two functions: to restrict the size of the dorsal mesoderm structure known as the organizer, and to promote the development of posterior mesoderm that populates the trunk and tail. Importantly, the organizer is a source of secreted Bmp antagonists that regulate Bmp-dependent ventral and posterior mesoderm patterning. Because the organizer impacts Bmp signaling activity, it is not clear whether functions attributed to zygotic Wnt signaling are in fact indirectly due to reduced Bmp activity. The objective of this thesis is to test the hypothesis that zygotic Wnt signaling plays two critical functions: to restrict the size of the organizer and to promote posterior mesoderm development in a Bmp-independent manner. To test this hypothesis, we characterized in depth the phenotypic defects of zebrafish embryos lacking Wnt8, the central ligand involved in zygotic Wnt-dependent mesoderm patterning. To identify Bmp-independent functions of Wnt8 signaling, we used double loss-of-function conditions to elevate Bmp signaling in embryos lacking Wnt8 function. Embryos were analyzed for the expression of a comprehensive set of mesoderm markers indicative of cell fates found in all spatial positions of the embryo. Our results show that, in addition to posterior mesoderm precursors being drastically reduced in Wnt8 morphants, anterior fates are disrupted as well. We found that increasing Bmp signaling largely has no effect on the Wnt8 morphant phenotype. However, slight rescue was observed in pronephric, heart tube, and vasculature precursors. We believe these results support the hypothesis that Wnt signaling maintains mesoderm progenitor cell populations, while Bmp signaling patterns mesoderm cell fates. Accordingly, Wnt8 signaling will appear to be epistatic to Bmp signaling during vertebrate axis patterning.

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In vertebrate embryonic development, correct specification of tissue fates along the dorsoventral (D/V) axis is known to require the secreted signaling ligand Wnt8. Wnt8 signaling promotes ventral fates and antagonizes the expansion of the dorsal domain known as the organizer. Maintenance of the organizer is critical for proper development as this tissue is known to produce inhibitors of Wnt and BMP (Bone Morphogenetic Protein) family ligands; BMPs are also known to play a major role in promoting ventral fates. In order to understand how Wnt8 antagonizes the organizer, we analyzed the epistatic relationship between Wnt8 and the transcriptional repressors Vent and Vox using zebrafish as a model organism. We found that Wnt8/β-catenin signaling directly regulates the transcriptional levels of vent and vox so that they can repress the transcription of dorsal genes on the ventral side of the embryo. To understand the contribution of Wnt8 towards ventral fate specification, we carefully analyzed its relationship with BMP signaling during gastrula stages. We found that bmp expression in the mesoderm is under the control of Wnt8 at mid-gastrulation and that regulation of bmp explains many of the ventral defects observed in wnt8 mutants. Antagonism of the expression of organizer-derived BMP inhibitors by Wnt8 also indirectly allows timely BMP signaling. Analysis of wnt8; bmp double mutants revealed an early unsuspected function of BMP in the antagonism of the organizer. Further, we uncovered a mechanism through which regulation of vent, vox and a related-gene ved expression by both Wnt8 and BMP antagonizes dorsal/axial mesoderm identity to preserve the integrity of ventral/non-axial tissues. In summary, we have revealed some of the mechanisms of Wnt8 function in D/V mesoderm patterning: it restricts the organizer domain by regulating vent and vox, it allows BMP induced differentiation through its inhibition of BMP antagonists derived from the organizer and it co-regulates vent, vox, and ved with BMP signaling to allow maintenance of the non-axial domain.

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Ulm, Univ., Diss., 2007.