Role of Fibroblast Growth Factor - 4 in the Early Mouse Embryo

Columbia University, New York NY

Investigators

Abstract

Papaioannou 9985953 Stem cells are self renewing. That is, they divide and give rise to a cell that differentiates as well as a cell that maintains its identity as a stem cell. Understanding how stem cells are regulated is fundamental to understanding how mutlicellular organisms form. Dr. Papioannou is investigating the potential role of growth factors in regulating stem cell populations. Given the critical role of stem cells in development, this work will lead to a deeper understanding of the regulation of embryo development. Fibroblast growth factors (FGFs) comprise a family of related signaling molecules that bind and activate fibroblast growth factor receptors (FGFRs). FGF-4, which is expressed in the inner cell mass (ICM) of the blastocyst and in the later epiblast, is essential for peri-implantation development. Mouse embryos lacking this factor through gene targeting of Fgf4 implant in the uterus but fail to undergo further development. The experiments proposed will investigate the potential role of FGF-4 as a stem cell factor in early embryos by examining three hypotheses: (1) FGF-4 is an autocrine proliferation or survival factor for the ICM. (2) FGF-4 promotes the differentiation of primitive endoderm. (3) FGF-4 is a paracrine stem cell factor for the diploid trophoblast. Dr. Papaioannou's first approach will be a detailed examination of cell number and differentiated cell distribution in mutant Fgf4 embryos throughout peri-implantation development. The second will be to attempt rescue of mutant effects by supplying exogenous recombinant FGF-4 to intact embryos. The third approach makes use of chimera analysis using both mutant embryonic stem (ES) cells combined with normal embryos and vice versa. Each of the hypotheses has specific predictions with respect to the cell composition of chimeras and the potential rescue of the mutant phenotype. Taken together, these studies will provide specific information about the in vivo effect of FGF-4 on stem cell populations of the early embryo and have general implications for the role of FGFs on the control of other embryonic or adult stem cell populations.