The bHLH-Zip transcription factor Tfeb is essential for placental vascularization

Tfcb is a member of the basic Helix-Loop-Helix-Zipper family of transcripti on factors. In vitro studies have shown that TFEB can bind DNA as a homodim er or as a heterodimer with three closely related family members: MITF, TFE 3 and TFEC. While mutations of Mitf have been shown to affect the developme nt of a number of cell types including melanocytes, osteoclasts, and masts cells, little is known about the phenotypic consequences of mutations at Tf e3, Tfcb and Tfec, Here we show that mice with a targeted disruption of Tfe b die between 9.5 and 10.5 days in embryonic development and have severe de fects in placental vascularization, Tfeb is expressed at low levels in the embryo but at high levels in the labyrinthine trophoblast cells of the plac enta. While labyrinthine cells are present in the mutant Tfeb placenta, the y fail to express VEGF, a potent mitogen required for normal vasculogenesis of the embryo and extraembryonic tissues. In Tfeb mutant embryos the embry onic vasculature forms normally but few vessels are seen entering the place nta and those that do enter fail to thrive and branch normally. Our results indicate that Tfeb plays a critical role in the signal transduction proces ses required for normal vascularization of the placenta.