Selective ablation of retinoid X receptor alpha in hepatocytes impairs their lifespan and regenerative capacity.
Retinoid X receptors (RXRs) are involved in a number of signaling pathways as heterodimeric partners of numerous nuclear receptors. Hepatocytes express high levels of the RXRalpha isotype, as well as several of its putative heterodimeric partners. Germ-line disruption (knockout) of RXRalpha has been shown to be lethal in utero, thus precluding analysis of its function at later life stages. Hepatocyte-specific disruption of RXRalpha during liver organogenesis has recently revealed that the presence of hepatocytes is not mandatory for the mouse, at least under normal mouse facility conditions, even though a number of metabolic events are impaired [Wan, Y.-J., et al. (2000) Mol. Cell. Biol. 20, 4436-4444]. However, it is unknown whether RXRalpha plays a role in the control of hepatocyte proliferation and lifespan. Here, we report a detailed analysis of the liver of mice in which RXRalpha was selectively ablated in adult hepatocytes by using the tamoxifen-inducible chimeric Cre recombinase system. Our results show that the lifespan of adult hepatocytes lacking RXRalpha is shorter than that of their wild-type counterparts, whereas proliferative hepatocytes of regenerating liver exhibit an even shorter lifespan. These lifespan shortenings are accompanied by increased polyploidy and multinuclearity. We conclude that RXRalpha plays important cell-autonomous function(s) in the mechanism(s) involved in the lifespan of hepatocytes and liver regeneration.
Imai
T
T
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Collège de France, BP 163, 67404 Illkirch Cedex, Communauté Urbaine de Strasbourg, France.
Jiang
M
M
Kastner
P
P
Chambon
P
P
Metzger
D
D
D000818:Animals; D016922:Cellular Senescence; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008115:Liver Regeneration; D051379:Mice; D018345:Mice, Knockout; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors