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Review
. 2024 Aug;46(8):e2300118.
doi: 10.1002/bies.202300118. Epub 2024 Jun 24.

Cited2 is a key regulator of placental development and plasticity

Marija Kuna  1   2 , Michael J Soares  1   2   3   4
Affiliations
Review

Cited2 is a key regulator of placental development and plasticity

Marija Kuna et al. Bioessays. 2024 Aug.

Abstract

The biology of trophoblast cell lineage development and placentation is characterized by the involvement of several known transcription factors. Central to the action of a subset of these transcriptional regulators is CBP-p300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). CITED2 acts as a coregulator modulating transcription factor activities and affecting placental development and adaptations to physiological stressors. These actions of CITED2 on the trophoblast cell lineage and placentation are conserved across the mouse, rat, and human. Thus, aspects of CITED2 biology in hemochorial placentation can be effectively modeled in the mouse and rat. In this review, we present information on the conserved role of CITED2 in the biology of placentation and discuss the use of CITED2 as a tool to discover new insights into regulatory mechanisms controlling placental development.

Keywords: CITED2; HIF1; TFAP2C; modulator; placentation; trophoblast.

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Conflict of interest statement

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

Fig. 1.
Fig. 1.. Hemochorial placentation.
Schematic diagrams showing placentation sites of the mouse, rat, and human. The mouse exhibits shallow intrauterine trophoblast cell invasion, whereas the rat and human possess deep intrauterine trophoblast cell invasion. Invasive trophoblast (IT) and extravillous trophoblast (EVT) cells are functional equivalents, and the junctional zone (JZ) of the rodent placentation site is homologous to the EVT cell column (CC) of human placentation site. Uterine-placental interface (UPI), labyrinth zone (LZ), decidua (Dec), natural killer (NK) cells, villous core (VC), syncytiotrophoblast (STB), cytotrophoblast (CTB), basal CTB (bCTB), villous CTB (vCTB), spiral arteries (SpA), endothelial cells (EC), and red blood cells (RBC). Modified from Soares et al., 2017 with permission.
Fig. 2.
Fig. 2.. CITED2 is expressed in both rat and human placentation sites.
A) Schematic showing the late gestation rat placentation site. Invasive trophoblast cells are depicted in green. B) In situ hybridization showing Cited2 transcript localization in a rat gestation day (gd) 18.5 placentation site (Scale bar, 500 μm). C) Schematic showing the late gestation human extravillous trophoblast (EVT) cell column (CC). Invasive EVT cells are depicted in green. D) In situ hybridization showing CITED2 transcript localization in first trimester (12 week) human placenta: CITED2, CDH1 (marker of basal cytotrophoblast, bCTB), NOTUM (marker of EVT cells) (Scale bar, 50 μm). Uterine-placental interface (UPI), junctional zone (JZ), labyrinth zone (LZ), decidua (Dec), natural killer (NK) cells, villous core (VC), syncytiotrophoblast (STB), cytotrophoblast (CTB), and villous CTB (vCTB). Modified from Kuna et al., 2023 with permission.
Fig. 3.
Fig. 3.. The CITED protein family conserved domains.
A) Location of conserved regions (CR) within the CITED family. B) Amino acid sequence alignment of CR2 domains for each member of the CITED family.
Fig. 4.
Fig. 4.. Schematic of CITED2 positive and negative actions on gene regulation.
A) CITED2 facilitation of transcription factor (TF) interaction with CREBBP /EP300 promoting gene activation. B) CITED2 interference of TF interaction with CREBBP /EP300 preventing TF-mediated gene activation.
See this image and copyright information in PMC

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