Cell Growth and Differentiation in the Vetebrate Embryo

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DESCRIPTION (provided by applicant): The defining feature of the mouse gastrula is the primitive streak, a dynamic structure through which epiblast cells ingress to generate nascent mesoderm and endoderm. Fate mapping studies have revealed that the primitive streak can be divided into three functional regions: the proximal streak that gives rise to germ cells and extraembryonic mesoderm; the distal streak that generates cardiac mesoderm and node-derived axial mesendoderm; and the middle streak that produces non-midline trunk mesoderm. The mouse mutation amnionless (amn) not only impairs epiblast growth, but also specifically disrupts the assembly and/or function of the middle primitive streak. The recent identification of the Amn gene shows that it encodes a novel type I transmembrane protein that is specifically expressed in the visceral endoderm during gastrulation. Thus Amn must act cell non-autonomously in the visceral endodemi to govern epiblast cell behaviors required for growth and the specification of the middle primitive streak. The extracellular region of Amn includes a cysteine rich (CR) motif with similarity to BMP-binding CR modules in proteins, such as Chordin, known to act as modulators of BMP signaling. These findings suggest that Amn may direct epiblast growth and the production of middle streak-derived trunk mesoderm by acting to modulate a BMP signaling pathway in the underlying visceral endoderm. This working model will be explored though a combination of biochemical, genetic, and embryological studies in cultured mammalian cells, mice, Xenopus, and Drosophila. In addition, the epiblast cell behavior(s) controlled by the "Amn pathway" in the visceral endoderm will be identified through a clonal lineage analysis and targeted transgene expression. Intriguingly, the two other known sites of Amn expression, kidney proximal tubule and intestine, are, like the visceral endoderm, polarized epithelia specialized for secretion and resorption. The finding of Amn homologues in both human and Drosophila indicate the Amn likely plays an evolutionarily conserved role in the development, differentiation, or function of these specialized cell types, often targets of human disease.