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Evolutionarily Conserved Molecular Cascade Controls Mammalian Trophectoderm Segregation

Review ofInitiation of a conserved trophectoderm program in human, cow, and mouse embryosfrom Nature by Stuart P. Atkinson

Our current understanding of the cell specification processes that occur during the early stages of mammalian preimplantation development mainly derives from mouse-based studies; however, gene-expression analyses have suggested that the mechanisms controlling early lineage specification may differ between mouse and other mammals such as humans [1-4] and cows [5].

Recent research from the laboratory of Kathy K. Niakan (The Francis Crick Institute, London, UK) set out to compare the first lineage differentiation events that occur during the morula stage (16-cell) embryo in multiple mammals, a time during which the outer cells initiate a trophectoderm placental progenitor program. Now, Gerri et al. report on the existence of an evolutionarily conserved molecular cascade that initiates trophectoderm segregation in human, cow, and mouse embryos [6]. 

After their comparative analysis of human, cow, and mouse embryos, the authors proposed that atypical protein kinase C (aPKC) activity at the cell-cell contact-free domain drives an apical-basal cell polarity change and initiates a trophectoderm program in the outer cells of the morula stage embryo. Specifically, aPKC sequesters angiomotin (AMOT), a modulator of the Hippo pathway, at the apical domain to inactivate Hippo signaling. This mechanism then promotes the translocation of Yes-associated protein 1 (YAP1) to the nucleus, where it combines with the Hippo signaling transcription factor TEA-domain family member 4 (TEAD4) to promote the transcriptional activation of a trophectoderm program (including the expression of the GATA3 transcription factor) that supports cavitation and blastocyst formation. The authors also discovered that small-molecule inhibition of aPKC or targeted aPKC protein depletion impaired trophectoderm initiation at the morula stage.

Overall, this exciting comparative study into early lineage specification suggests that a conserved mechanism induces trophectoderm segregation in early-stage human, mouse, and cow embryos, and perhaps most mammals.

For more on the earliest lineage specification events occurring in mammalian embryos, stay tuned to the Stem Cells Portal!


  1. Niakan KK and Eggan K, Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns relative to the mouse. Developmental Biology 2013;375:54-64.
  2. Fogarty NME, McCarthy A, Snijders KE, et al., Genome editing reveals a role for OCT4 in human embryogenesis. Nature 2017;550:67-73.
  3. Blakeley P, Fogarty NME, del Valle I, et al., Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. Development 2015;142:3151.
  4. Petropoulos S, Edsgärd D, Reinius B, et al., Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos. Cell 2016;165:1012-1026.
  5. Berg DK, Smith CS, Pearton DJ, et al., Trophectoderm Lineage Determination in Cattle. Developmental Cell 2011;20:244-255.
  6. Gerri C, McCarthy A, Alanis-Lobato G, et al., Initiation of a conserved trophectoderm program in human, cow and mouse embryos. Nature 2020;587:443