Essential Requirement of CCAAT/Enhancer Binding Proteins in Embryogenesis

Abstract

The CCAAT/enhancer binding proteins C/EBPα and C/EBPβ are related transcription factors that are important for the function of various organs in the postnatal mouse. Gene replacement and tissue culture experiments have suggested partial redundancy of both transcription factors. Here we show that mouse embryos deficient of both C/EBPα and C/EBPβ (C/EBPαβ^−/−) die between embryonic day 10 (E10) and E11 and display defective placentas. In situ hybridization revealed that C/EBPα and C/EBPβ are coexpressed in the chorionic plate at E9.5 and later in the trophoblasts of the labyrinthine layer. In C/EBPαβ^−/− placentas, allantoic blood vessels invaded the chorion; however, vessel expansion and development of the labyrinthine layer was impaired. Furthermore, a single copy of either C/EBPα in the absence of C/EBPβ or C/EBPβ in the absence of C/EBPα is sufficient to complete development, suggesting complementation of these C/EBPs during embryogenesis. A single copy of C/EBPα in the absence of C/EBPβ, however, fails to rescue survival after birth, suggesting haploinsufficiency of C/EBPα in newborns. Our data thus reveal novel essential, redundant, and dosage dependent functions of C/EBPs.

We are indebted to E. Sterneck (NCI, Frederick, Md.) for generously providing C/EBPβ^+/− mice and G. Darlington (Baylor College of Medicine, Houston, Tex.) for generously providing C/EBPα^+/− mice. We thank T. Müller and C. Birchmeier (Max Delbrueck Center for Molecular Medicine, Berlin, Germany) for valuable discussions and comments on the manuscript. We thank the members of Leutz lab for discussions. We are also grateful to E. Sterneck, U. Borgmeyer, D. Riethmacher, M. Soares, R. Evans, and E. E. Voest for providing cDNA probes and to J. Rossant for providing the TS cell line that served as a valuable control during the preparation of the manuscript.