In Vivo Function and Evolution of the Eutherian-Specific Pluripotency Marker UTF1

Embryogenesis in placental mammals is sustained by exquisite interplay between the embryo proper and placenta. UTF1 is a developmentally regulated gene expressed in both cell lineages. Here, we analyzed the consequence of loss of the UTF1 gene during mouse development. We found that homozygous UTF1 mutant newborn mice were significantly smaller than wild-type or heterozygous mutant mice, suggesting that placental insufficiency caused by the loss of UTF1 expression in extra-embryonic ectodermal cells at least in part contributed to this phenotype. We also found that the effects of loss of UTF1 expression in embryonic stem cells on their pluripotency were very subtle. Genome structure and sequence comparisons revealed that the UTF1 gene exists only in placental mammals. Our analyses of a family of genes with homology to UTF1 revealed a possible mechanism by which placental mammals have evolved the UTF1 genes.This study was supported in part by the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), and mostly by the Support Program for the Strategic Research Foundation at Private Universities, 2008–2012. This study was performed as a part of the Core Research for Evolutional Science and Technology (CREST) Agency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

<i>In Vivo</i> Function and Evolution of the Eutherian-Specific Pluripotency Marker UTF1

<div><p>Embryogenesis in placental mammals is sustained by exquisite interplay between the embryo proper and placenta. <i>UTF1</i> is a developmentally regulated gene expressed in both cell lineages. Here, we analyzed the consequence of loss of the <i>UTF1</i> gene during mouse development. We found that homozygous <i>UTF1</i> mutant newborn mice were significantly smaller than wild-type or heterozygous mutant mice, suggesting that placental insufficiency caused by the loss of <i>UTF1</i> expression in extra-embryonic ectodermal cells at least in part contributed to this phenotype. We also found that the effects of loss of <i>UTF1</i> expression in embryonic stem cells on their pluripotency were very subtle. Genome structure and sequence comparisons revealed that the <i>UTF1</i> gene exists only in placental mammals. Our analyses of a family of genes with homology to UTF1 revealed a possible mechanism by which placental mammals have evolved the <i>UTF1</i> genes.</p></div

The <i>UTF1</i> gene is present only in the genomes of eutherian (placental) mammals.

<p>(A) Genomic organizations surrounding the <i>UTF1</i> locus in mammals and their corresponding genomic regions in other organisms. Black boxes indicate regions without available genomic sequences. (B) VISTA Browser (VGB2.0) plot of the 65.5 kb interval (ch10∶134,506,934-134,572,432) containing <i>KNDC1</i>, <i>UTF1</i> and <i>VENTX</i> genes in the human genome. Conservation plots for elephant (top panel) mouse (second panel), opossum (third panel) and wallaby (bottom panel), with respect to human, are shown in the coordinates of the human sequence (horizontal axis). Dark blue boxes indicate portions with unavailable DNA sequences in the database.</p

Phenotypes of <i>UTF1</i> homozygous mutant mice with a mixed genetic background of C57BL/6J (25%) and ICR (75%).

<p>(A) Weight of viable <i>UTF1</i> homozygous mutant mice generated by intercrossing heterozygous mutant mice that had been backcrossed twice with wild-type ICR mice. These analyses revealed that adult <i>UTF1</i> homozygous mutant mice (4-weeks-old) were viable, but significantly smaller than corresponding wild-type and heterozygous mutant mice. Data represent the mean with SD (n = 4). **, p<0.01. (B) Intercrosses between <i>UTF1</i> homozygous and heterozygous mutant mice. These intercrosses showed that the <i>UTF1</i> homozygous mutation with a mixed mouse genetic background did not affect fertility, but led to the generation of small mice. Mouse weights were examined at 4 weeks after birth. Data represent the mean with SD (n = 4). *, p<0.05;</p