Loss of Cited2 affects trophoblast formation and vascularization of the mouse placenta

Abstract

Cited2 is widely expressed in the developing embryo and in extraembryonic tissues including the placenta. Gene expression can be induced by a number of factors; most notably by the hypoxia inducible transcription factor, HIF1, under low oxygen conditions. Cited2 encodes for a transcriptional co-factor that in vitro can act as both a positive and negative regulator of transcription. This function is due to its interaction with CBP/p300 and appears to depend on whether Cited2 enables CBP/p300 to interact with the basic transcriptional machinery, or if its binding prevents such an interaction from occurring. Here, we report a novel function for Cited2 in placenta formation, following gene deletion in mouse. In the absence of Cited2 the placenta and embryo are significantly small from 12.5 and 14.5 dpc respectively, and death occurs in utero. Cited2 null placentas have fewer differentiated trophoblast cell types; specifically there is a reduction in trophoblast giant cells, spongiotrophoblasts and glycogen cells. In addition, the fetal vasculature of the placenta is disorganised and there are fewer anastomosing capillaries. Given that Cited2 is expressed in both trophoblasts and the fetal vasculature, the observed defects fit well with the sites of gene expression. We conclude that Cited2 is required for normal placental development and vascularisation, and hence for embryo viability.

Gonadal defects in Cited2 -mutant mice indicate a role for SF1 in both testis and ovary differentiation

“…Further, we and others show that the delay and recovery of male (Val et al, 2007), and female (this study) transcriptional programs correlate with a delay and recovery of Sf1 levels. However, we cannot exclude the potential influence of low oxygen and nutrient levels caused by placental insufficiency in these mice (Withington et al, 2006), nor the potential for Cited2 to influence other genes important for testis or ovarian development.…”

“…Embryos lacking Cited2 die between 13.5 and 17.5 dpc (Weninger et al, 2005) with multiple developmental defects including cardiac malformations and exencephaly (Bamforth et al, 2001, Barbera et al, 2002, Yin et al, 2002. Placental insufficiency, which impacts on embryo growth between 12.5 and 14.5 dpc, is the likely cause of death (Withington et al, 2006). However, these defects do not appear to have a major influence on the early stages of gonadal development as testis morphology has previously been reported to be normal prior to death in embryos homozygous for a different Cited2 knockout allele to the one used in this study (Bamforth et al, 2001;Val et al, 2007).…”

“…It is possible that differences in SF1 levels, or background strains, between our Cited2 -/-model and the Sf1-haploinsufficient mice could result in a more severe delay in testis development and disrupted cord formation. Alternatively, the cord defects may be caused or amplified by deprivations resulting from placental insufficiency in these mice (Withington et al, 2006), or by loss of an unknown Cited2-regulated factor required for cord organisation.…”

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…”

Cited2 is required for normal hematopoiesis in the murine fetal liver

“…Deletion of Cited2 gene results in embryonic lethality in the mid to late gestation with embryos displaying cardiac malformations, neural tube defects, 7 adrenal agenesis, [8][9][10] left-right patterning defects, 9,11 and placental defects. 12 Further mechanistic studies have provided evidence that Cited2 plays pivotal roles in these processes through its transcriptional modulator functions for HIF-1 8,13 or AP-2␣ signaling. [9][10][11] Accumulated evidence has implicated the role of Cited2 in hematopoiesis because Bmi-1, which is essential for adult hematopoietic stem cell self-renewal, 14 is induced by Cited2 in mouse embryonic fibroblast (MEF) cells.…”