The transcriptional co-repressor TLE3 regulates development of trophoblast giant cells lining maternal blood spaces in the mouse placenta

Abstract

TLE3 is a transcriptional co-repressor that interacts with several DNA-binding repressors, including downstream effectors of the Notch signaling pathway. We generated Tle3-deficient mice and found that they die in utero and their death is associated with abnormal development of the placenta with major defects in the maternal vasculature. In the normal placenta, maternal blood spaces are lined, not as usual in the mammalian circulation by endothelial cells, but rather by specialized embryo-derived cells of the trophoblast cell lineage named trophoblast giant cells (TGC). Tle3 mRNA is expressed in those specialized TGC and Tle3 mutants show severe defects in differentiation of TGC-lined channels and lacunar spaces that take blood out of the labyrinth zone of the placenta and into the uterine veins. The mutants also show somewhat milder defects on the arterial-side of the maternal vascular circuit in spiral arteries and canals that take blood into the labyrinth. Notch2 and Tle3 expression patterns overlap in several TGC subtypes and we found that Tle3 and Notch2 mutants have some overlapping features. However, they also show differences implying that TLE3 may mediate some but not all of the effects of Notch2 signaling during placenta development. Therefore, formation of the different types of maternal blood spaces by different TGC subtypes is regulated by distinct molecular mechanisms.

Three-dimensional cultures of trophoblast stem cells autonomously develop vascular-like spaces lined by trophoblast giant cells

“…Given the complexity of these interactions, it is not surprising that pregnancy-related complications occur in humans with defects in the maternal vascular space but associated with the trophoblast compartment including preeclampsia and placenta abruption (Kaufmann et al, 2003;Rossant and Cross, 2001). Likewise, there are several examples of mouse mutants with defects in the maternal blood compartment (Gasperowicz et al, 2013b;Guzman-Ayala et al, 2004;Scott et al, 2000), as recently reviewed (Rai and Cross, 2014).…”

“…The maternal vascular network in the placenta is best described in mice and is lined by five subtypes of trophoblast giant cells (TGCs) which share properties of being large, polyploid cells arising from endoreduplication and expression of a complex array of hormones (Gasperowicz et al, 2013b;Simmons et al, 2007). Blood enters the placenta through radial arteries that then branch into several spiral arteries within the decidua (Adamson et al, 2002).…”

“…In culture, retinoic acid promotes development of P-TGCs but suppresses formation of S-TGCs, Ch-TGCs and C-TGCs (Simmons et al, 2007;Yan et al, 2001). Deletion of transcription factor Tle3 leads to reduction in number of Prl2c2/Plf-positive P-TGCs and Ch-TGCs (Gasperowicz et al, 2013b). Notch2 promotes differentiation of TGCs though more on the arterial side of the maternal vascular space (Gasperowicz et al, 2013b); Hamada et al, 1999;Hunkapiller et al, 2011).…”

Plac1 Expression Pattern at the Mouse Fetomaternal Interface and Involvement in Trophoblast Differentiation

“…The sense probe was incubated with the serial sections and deemed as the negative control. The marker gene trophoblast-specific protein α ( Tpbp ) was used as the antisense probe to label the EPC or spongiotrophoblast layer [13]. Tissues from five different female mice were employed at each stage of pregnancy.…”

Tpbpa mediated deletion of Tfap2c leads to deregulation of MAPK, P21, AKT and subsequent placental growth arrest

“…Around E8.5, a subset of cells within EPC starts to express the gene Tpbpa (trophoblast-specific protein α) and differentiate into the junctional zone (JZ) of the placenta (Carney et al, 1993;Lescisin et al, 1988;Simmons et al, 2007). The JZ comprises spongiotrophoblast cells (SpTs) and glycogen trophoblast cells (GCs) interspersed by several blood canals lined by trophoblast giant cells (TGCs) called canal TGCs (C-TGCs) and the channel TGCs (Ch-TGCs) (Adamson et al, 2002;Gasperowicz et al, 2013;Guillemot et al, 1994). Aside from forming SpT and GCs, TPBPA + cells give rise to all spiral artery-associated TGCs (SpA-TGCs) and half of C-TGCs (Simmons et al, 2007).…”