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Mechanisms of early placental development in mouse and humans


The importance of the placenta in supporting mammalian development has long been recognized, but our knowledge of the molecular, genetic and epigenetic requirements that underpin normal placentation has remained remarkably under-appreciated. Both the in vivo mouse model and in vitro-derived murine trophoblast stem cells have been invaluable research tools for gaining insights into these aspects of placental development and function, with recent studies starting to reshape our view of how a unique epigenetic environment contributes to trophoblast differentiation and placenta formation. These advances, together with recent successes in deriving human trophoblast stem cells, open up new and exciting prospects in basic and clinical settings that will help deepen our understanding of placental development and associated disorders of pregnancy.

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Fig. 1: Key stages of mouse and human placental development.
Fig. 2: Transcriptional networks in trophoblast stem cells.
Fig. 3: Distinct epigenetic dynamics and features of the first cell lineages in mice.
Fig. 4: The placenta affects the development of particular embryonic organ systems.
Fig. 5: Novel in vitro tools for studying early mammalian development.


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The authors’ programme of work is funded by a Next Generation Fellowship from the Centre for Trophoblast Research to C.W.H.; by a Tier I Canada Research Chair grant to M.H.; by the Magee Prize, funded by the Richard King Mellon Foundation; and by the Alberta Children’s Hospital Research Institute.

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Nature Reviews Genetics thanks S. Paul, J. Rossant and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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W.D. and M.H. contributed to discussion of the content. All authors researched data for the article. The bulk of the article was written by M.H. and W.D., with essential contributions on human development and global epigenome studies by C.W.H. All authors reviewed and/or edited the article before submission.

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Correspondence to Myriam Hemberger or Wendy Dean.

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Supplementary information



The early cell lineage that arises at the blastocyst stage and gives rise to most extra-embryonic tissues, most notably those of the placenta.


The middle layer of the uterine wall, which consists of smooth muscle cells that are important for contraction.


The phenomenon of cells or tissues being genetically different and hence distinct from each other in terms of cell surface antigen repertoire, leading to immunological incompatibility.

Haemochorial placentation

The anatomical arrangement in placentas in which trophoblast-lined villi are directly exposed to maternal blood.


The process by which endometrial stromal fibroblasts become specialized secretory decidual cells during pregnancy.


The complex of DNA, RNA and proteins (mostly histones) that collectively comprise the chromosomes.


The sum total of all modifications to DNA, or to DNA-associated RNA and proteins, that permit interpretation of the genome to instruct cell identity and function.


The process of cell–cell fusion that leads to the formation of a multi-nucleate cell. It occurs when cytotrophoblast cells fuse during placental development to form syncytiotrophoblast.

Imprinted genes

The relatively small collection of genes whose expression is solely based on parent-of-origin inheritance of the allele.


Changes in the modification status of a cytosine (that is, DNA methylation, hydroxymethylation or derivatives), usually found in the context of CpG dinucleotides, between successive cell divisions or generations.

Transgenerational inheritance

Inheritance across multiple successive (>2) generations of instructive elements of the epigenome, found in germ cells (oocytes or sperm).

CpG islands

(CGIs). Regions of the genome in which the CpG frequency is greater than 50% GC content over at least 200 base pairs.

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Hemberger, M., Hanna, C.W. & Dean, W. Mechanisms of early placental development in mouse and humans. Nat Rev Genet 21, 27–43 (2020).

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