Regulation Of Mouse Embryonic And Extraembryonic Morphogenesis By Zfp568 And Trim28

Abstract

In mammals, extraembryonic tissues are critical for sustaining embryonic life inside the uterus, providing nourishment and secreting factors to maintain pregnancy. However, our understanding of the genes controlling the morphogenesis of these tissues is still limited. chato, an ENU allele disrupting the mouse Kruppel-associated box (KRAB) zinc finger protein ZFP568, causes unique defects in the morphogenesis of extraembryonic tissues including yolk sac ruffling, incomplete formation of a yolk sac vascular plexus, and failure to form a normal placenta. Most chato embryos have an expanded chorionic ectoderm that, in extreme cases, prevents the closure of the ectoplacental cavity. Interestingly, I found that the severity of yolk sac defects in chato embryos correlated with trophoblast malformations, suggesting that all extraembryonic defects in chato mutants have a common developmental origin. To address the requirements of Zfp568 in different extraembryonic lineages, I analyzed chimeric embryos generated by both tetraploid complementation assays and by the use of a reversible allele of Zfp568 in combination with Cre lines. My results indicate that ZFP568 is required in the extraembryonic mesoderm to regulate the morphogenesis of the yolk sac and placenta, and support a previously undescribed role of the extraembryonic mesoderm in the morphogenesis of extraembryonic tissues. Characterization and positional cloning of chatwo, another ENU-induced mutation that causes similar morphogenetic defects to those of Zfp568 mutants, has shed light on the molecular mechanisms utilized by ZFP568 to control morphogenesis. chatwo creates a hypomorphic mutation in TRIM28, a RBCC-bromo domain protein that recruits chromatin modifying enzymes and binds to KRAB zinc finger proteins. Results from genetic interaction studies, and analysis of Trim28 mosaic embryos suggest that TRIM28 is required as a cofactor of ZFP568 in embryonic tissues to regulate embryo morphogenesis. Despite the fact that over 300 KRAB zinc finger proteins are found in genomes of tetrapod vertebrates, reasons for the rapid expansion of the KRAB zinc finger family remain unknown. My findings suggest that some KRAB zinc finger proteins, including ZFP568, may have evolved specialized functions for the control of early embryonic development in the mouse.