Cited1 Is Required in Trophoblasts for Placental Development and for Embryo Growth and Survival

Abstract

Cited1 is a transcriptional cofactor that interacts with Smad4, estrogen receptors ␣ and ␤, TFAP2, and CBP/p300. It is expressed in a restricted manner in the embryo as well as in extraembryonic tissues during embryonic development. In this study we report the engineering of a loss-of-function Cited1 mutation in the mouse. Cited1 null mutants show growth restriction at 18.5 days postcoitum, and most of them die shortly after birth. Half the heterozygous females, i.e., those that carry a paternally inherited wild-type Cited1 allele, are similarly affected. Cited1 is normally expressed in trophectoderm-derived cells of the placenta; however, in these heterozygous females, Cited1 is not expressed in these cells. This occurs because Cited1 is located on the X chromosome, and thus the wild-type Cited1 allele is not expressed because the paternal X chromosome is preferentially inactivated. Loss of Cited1 resulted in abnormal placental development. In mutants, the spongiotrophoblast layer is irregular in shape and enlarged while the labyrinthine layer is reduced in size. In addition, the blood spaces within the labyrinthine layer are disrupted; the maternal sinusoids are considerably larger in mutants, leading to a reduction in the surface area available for nutrient exchange. We conclude that Cited1 is required in trophoblasts for normal placental development and subsequently for embryo viability.

Imprinted genes in mouse placental development and the regulation of fetal energy stores

“…The junctional zone of mutant placenta was enlarged with a concomitant decrease in labyrinthine area. Vascularisation of the labyrinth was defective, with increased sinusoidal spaces resulting in a reduced surface area for nutrient transport (Rodriguez et al 2004). Consistent with placental insufficiency, mutant embryos were asymmetrically growth restricted during late gestation, with the majority of mutants dying in the neonatal period and survivors exhibiting catch-up growth within 8 weeks of birth (Rodriguez et al 2004, Novitskaya et al 2011.…”

Origin and characteristics of glycogen cells in the developing murine placenta

“…Over the past few years, several groups investigating placental development have reported placentomegaly often associated with expansion of the Jz (Takahashi et al, 2000;Georgiades et al, 2001;Tanaka et al, 2001;Frank et al, 2002;Yang et al, 2003;Rodriguez et al, 2004). To our knowledge, there has not been a thorough investigation of the cellular composition of the Jz.…”

Development and function of trophoblast giant cells in the rodent placenta

“…Mutants die by E10.5 with reduced spongiotrophoblast and TGC (Nadra et al, 2006, Wang et al, 2007 HIF bHLH/PAS transcription factors composed of HIFα and HIFβ/Arnt subunits Arnt -/-and Hif1α -/-Hif2α -/-die by E10.5 with TGC number increased, smaller ectoplacental cone and reduced spongiotrophoblast (Abbott and Buckalew, 2000, Adelman et al, 2000, Cowden Dahl et al, 2005 Cited 1 CBP/p300-interacting transactivator Mutants die shortly after birth, spongiotrophoblast layer irregular in shape and enlarged (Rodriguez et al, 2004) Cited 2 CBP/p300-interacting transactivator Mutants die by E14.5 with reduced spongiotrophoblast, glycogen trophoblast cells and TGCs (Withington et al, 2006) , Jaquemar et al, 2003, Tamai et al, 2000 Connexin 31 Connexin; Gap junction protein 60% mutants die between E10.5 and 13.5 TGC number increased, spongiotrophoblast and labyrinth decreased (Kibschull et al, 2004, Plum et al, 2001 Mutants die by E9.5 with disorganized extraembryonic tissues and the ectoplacental and excocoelomic cavities are not formed (Monkley et al, 2000) TGC terminal differentiation…”