title: Compensatory embryonic response to allele-specific inactivation of the murine X-linked gene Hcfc1.
abstract: Early in female mammalian embryonic development, cells randomly inactivate one of the two X chromosomes to achieve overall equal inactivation of parental X-linked alleles. Hcfc1 is a highly conserved X-linked mouse gene that encodes HCF-1 - a transcriptional co-regulator implicated in cell proliferation in tissue culture cells. By generating a Cre-recombinase inducible Hcfc1 knock-out (Hcfc1(lox)) allele in mice, we have probed the role of HCF-1 in actively proliferating embryonic cells and in cell-cycle re-entry of resting differentiated adult cells using a liver regeneration model. HCF-1 function is required for both extraembryonic and embryonic development. In heterozygous Hcfc1(lox/+) female embryos, however, embryonic epiblast-specific Cre-induced Hcfc1 deletion (creating an Hcfc1(epiKO) allele) around E5.5 is well tolerated; it leads to a mixture of HCF-1-positive and -negative epiblast cells owing to random X-chromosome inactivation of the wild-type or Hcfc1(epiKO) mutant allele. At E6.5 and E7.5, both HCF-1-positive and -negative epiblast cells proliferate, but gradually by E8.5, HCF-1-negative cells disappear owing to cell-cycle exit and apoptosis. Although generating a temporary developmental retardation, the loss of HCF-1-negative cells is tolerated, leading to viable heterozygous offspring with 100% skewed inactivation of the X-linked Hcfc1(epiKO) allele. In resting adult liver cells, the requirement for HCF-1 in cell proliferation was more evident as hepatocytes lacking HCF-1 fail to re-enter the cell cycle and thus to proliferate during liver regeneration. The survival of the heterozygous Hcfc1(epiKO/+) female embryos, even with half the cells genetically compromised, illustrates the developmental plasticity of the post-implantation mouse embryo - in this instance, permitting survival of females heterozygous for an X-linked embryonic lethal allele.
authors.affiliation: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Minocha
authors.affiliation: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Tzu-Ling
authors.initials: TL
authors.lastname: Sung
authors.affiliation: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Dominic
authors.initials: D
authors.lastname: Villeneuve
authors.affiliation: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lammers
authors.affiliation: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: winship.herr@unil.ch.
authors.forename: Winship
authors.initials: W
authors.lastname: Herr
mesh_terms: D000483:Alleles; D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D050172:Genes, X-Linked; D051863:Host Cell Factor C1 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D051863:Host Cell Factor C1
keywords: Cell proliferation; HCF-1; Liver regeneration; Post-implantation development; X chromosome inactivation