DISRUPTION OF THE HNF-4 GENE, EXPRESSED IN VISCERAL ENDODERM, LEADS TO CELL-DEATH IN EMBRYONIC ECTODERM AND IMPAIRED GASTRULATION OF MOUSE EMBRYOS

Expression of HNF-4, a transcription factor in the steroid hormone rec eptor superfamily, is detected only in the visceral endoderm of mouse embryos during gastrulation and is expressed in certain embryonic tiss ues from 8.5 days of gestation. To examine the role of HNF-4 during em bryonic development, we disrupted the gene in embryonic stem cells and found that the homozygous loss of functional HNF-4 protein was an emb ryonic lethal. Cell death was evident in the embryonic ectoderm at 6.5 days when these cells normally initiate gastrulation. As assessed by expression of Brachyury and HNF-3 beta, primitive streak formation and initial differentiation of mesoderm do occur, but with a delay of sim ilar to 24 hr. Development of embryonic structures is severely impaire d. These results demonstrate that the expression of HNF-4 in the visce ral endoderm is essential for embryonic ectoderm survival and normal g astrulation.