Abstract
Trophoblasts are the first cell type to be specified during embryogenesis, and they are essential for placental morphogenesis and function. Trophoblast stem (TS) cells are the progenitor cells for all trophoblast lineages; control of TS cell differentiation into distinct trophoblast subtypes is not well understood. Mice lacking the transcription factor OVO-like 2 (OVOL2) fail to produce a functioning placenta, and die around embryonic day 10.5, suggesting that OVOL2 may be critical for trophoblast development. Therefore, our objective was to determine the role of OVOL2 in mouse TS cell fate. We found that OVOL2 was highly expressed in mouse placenta and differentiating TS cells. Placentas and TS cells lacking OVOL2 showed poor trophoblast differentiation potential, including increased expression of stem-state associated genes (Eomes, Esrrb, Id2) and decreased levels of differentiation-associated transcripts (Gcm1, Tpbpa, Prl3b1, Syna). Ectopic OVOL2 expression in TS cells elicited precocious differentiation. OVOL2 bound proximate to the gene encoding inhibitor of differentiation 2 (ID2), a dominant negative helix-loop-helix protein, and directly repressed its activity. Overexpression of ID2 was sufficient to reinforce the TS cell stem state. Our findings reveal a critical role of OVOL2 as a regulator of TS cell differentiation and placental development, in-part by coordinating repression of ID2.
Highlights
Trophoblast is the first cell type to become specified during early embryogenesis
Our findings reveal a critical role of OVO-like 2 (OVOL2) as a regulator of trophoblast stem (TS) cell differentiation and placental development, in-part by coordinating repression of inhibitor of differentiation 2 (ID2)
OVOL2 Is Highly Expressed in Mouse Placenta
Summary
Trophoblast is the first cell type to become specified during early embryogenesis. These cells form the epithelial portion of the placenta and perform crucial functions that support fetal growth and development. Cells, which can be derived from the early embryo and are a powerful tool for determining cell fate decisions in extraembryonic lineages. Precise spatial and temporal control of TS cell differentiation is fundamental for normal placental morphogenesis and function [1], but the regulation of TS cell differentiation is poorly understood. Mouse models have been instrumental in advancing our understanding of TS cell development and providing insight into the morphology and function of the placenta [2,3]. The regulation of mouse TS cell maintenance and differentiation has been extensively studied, since culture conditions that facilitate long-term TS cell culture and differentiation in this species have been known for several decades, Cells 2020, 9, 840; doi:10.3390/cells9040840 www.mdpi.com/journal/cells
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