Embryonic Lethality and Fetal Liver Apoptosis in Mice Lacking All Three Small Maf Proteins

   1. Hiromi Yamazakia,
   2. Fumiki Katsuokab,
   3. Hozumi Motohashic,
   4. James Douglas Engeld and
   5. Masayuki Yamamotoa

   1.
      aDepartment of Medical Biochemistry
   2.
      bDepartment of Bioscience for Drug Discovery
   3.
      cCenter for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
   4.
      dDepartment of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA

ABSTRACT

Embryogenesis is a period during which cells are exposed to dynamic changes of various intracellular and extracellular stresses. Oxidative stress response genes are regulated by heterodimers composed of Cap'n'Collar (CNC) and small Maf proteins (small Mafs) that bind to antioxidant response elements (ARE). Whereas CNC factors have been shown to contribute to the expression of ARE-dependent cytoprotective genes during embryogenesis, the specific contribution of small Maf proteins to such gene regulation remains to be fully examined. To delineate the small Maf function in vivo, in this study we examined mice lacking all three small Mafs (MafF, MafG, and MafK). The small Maf triple-knockout mice developed normally until embryonic day 9.5 (E9.5). Thereafter, however, the triple-knockout embryos showed severe growth retardation and liver hypoplasia, and the embryos died around E13.5. ARE-dependent cytoprotective genes were expressed normally in E10.5 triple-knockout embryos, but the expression was significantly reduced in the livers of E13.5 mutant embryos. Importantly, the embryonic lethality could be completely rescued by transgenic expression of exogenous MafG under MafG gene regulatory control. These results thus demonstrate that small Maf proteins are indispensable for embryonic development after E9.5, especially for liver development, but early embryonic development does not require small Mafs.
FOOTNOTES

          o Received 8 November 2011.
          o Accepted 1 December 2011.
    * Address correspondence to Masayuki Yamamoto, masiyamamoto{at}med.tohoku.ac.jp.
    *

      H. Yamazaki and F. Katsuoka contributed equally to this article.
    *

      Published ahead of print 12 December 2011
    *

      Supplemental material for this article may be found at http://mcb.asm.org/.

    * Copyright © 2012, American Society for Microbiology. All Rights Reserved.

