DEVELOPMENTAL-SPECIFIC ACTIVITY OF THE FGF-4 ENHANCER REQUIRES THE SYNERGISTIC ACTION OF SOX2 AND OCT-3

Fibroblast growth factor 4 (FGF-4) has been shown to be a signaling mo lecule whose expression is essential for postimplantation mouse develo pment and, at later embryonic stages, for limb patterning and growth. The FGF-4 gene is expressed in the blastocyst inner cell mass and late r in distinct embryonic tissues but is transcriptionally silent in the adult. In tissue culture FGF-4 expression is restricted to undifferen tiated embryonic stem (ES) cells and embryonal carcinoma (EC) cell lin es. Previously, we determined that EC cell-specific transcriptional ac tivation of the FGF-4 gene depends on a synergistic interaction betwee n octamer-binding proteins and an EC-specific factor, Fx, that bind ad jacent sites on the FGF-4 enhancer. Through the cloning and characteri zation of an F9 cell cDNA we now show that the latter activity is Sox2 , a member of the Sry-related Sox factors family. Sox2 can form a tern ary complex with either the ubiquitous Oct-1 or the embryonic-specific Oct-3 protein on FGF-4 enhancer DNA sequences. However, only the Sox2 /Oct-3 complex is able to promote transcriptional activation. These fi ndings identify FGF-4 as the first known embryonic target gene for Oct -3 and for any of the Sox factors, and offer insights into the mechani sms of selective gene activation by Sox and octamer-binding proteins d uring embryogenesis.