Gastrulation is a fundamental developmental process, and in the mouse it coordinates complex cell and tissue movements with cell growth and proliferation to reorganize and differentiate the embryonic ectoderm into the definitive ectoderm, mesoderm, and endoderm germ layers of the fetus. The genetic pathways directing gastrulation are only beginning to be unraveled by both targeted and random mutagenesis in the mouse and fish. Intriguingly, a number of gastrulation stage mouse mutants have been discovered through the targeted disruption of genes that are known, through their involvement with human disease, to participate in the basic cellular processes of proliferation, differentiation, and signal transduction. Recent examples include the fibroblast growth factor receptor (Fgfr-1), Brca1, Brca2, Huntington's disease homologue (Hdh), and the tumor suppressor Smad4/Dpc4. Thus the study of novel gastrulation stage mouse mutants is likely to lead to the identification of genes that serve pivotal functions in the coordination of cell growth, proliferation, and differentiation. The subject of this proposal is amnionless (amn), a recessive transgene insertional mutation that disrupts the assembly of the middle streak, this portion of the primitive streak that gives rise to non-axial embryonic mesoderm, such as somitic mesoderm. This novel phenotype reveals that the formation of the middle streak is mediated by a previously unknown pathway, one that is genetically separable from those directing the formation and specification of the proximal and distal streak regions. Therefore, a disrupted gene at the amn locus must play a key role in this pathway. Chimera analyses have shown that this gene, the amn gene, functions in the visceral endoderm to direct the formation of the middle streak and thus, that amn defines a new role for the visceral endoderm during gastrulation. The primary objective of this proposal is to positionally clone the amn gene.
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