A pinboard by
Alvaro Plaza Reyes

PhD Student, Karolinska Institutet


Over the past decades, a lot of effort has been put into elucidating the molecular pathways controlling the first lineage segregations in the mammalian preimplantation embryo. Due to its great accessibility and simplicity, the mouse model was the one that was most explored. However, as recent studies have shown, there might be essential differences between the mouse and other mammalians species like the human. Based on what was learned from the mouse model and building up on our recently published single-cell transcriptomic roadmap of the early human embryo, we aim to investigate which molecular pathways control the first lineage segregations in the human preimplantation embryo with a special emphasis in the potential role of Hippo pathway during trophectoderm-inner cell mass segregation. For that purpose, we will make use of state-of-the-art gene editing techniques in both human embryonic stem cells and early human embryo to interfere with selected molecular players and test their implications by studying the lineage commitment of edited cells and any possible downstream transcriptional effects in developing human embryos.


Roles and regulations of Hippo signaling during preimplantation mouse development.

Abstract: During preimplantation development, mouse embryos form two types of cells, the trophoectoderm (TE) and inner cell mass (ICM), by the early blastocyst stage. This process does not require maternal factors localized in the zygotes, and embryos self-organize at the blastocyst stage through intercellular communications. In terms of the mechanisms of cell fate specification, three historical models have been proposed: the positional model, and the original and newer versions of the polarity model. Recent studies have revealed that the intercellular Hippo signaling pathway plays a central role in the specification of the first cell fates. Hippo signaling is active in the inner cells but inactive in the outer cells. The Hippo-active inner and Hippo-inactive outer cells take the fates of the ICM and the TE, respectively. At the 32-cell stage, E-cadherin-mediated cell-cell adhesion and cell polarization by the Par-aPKC system activates and inactivates the Hippo pathway, respectively. Both mechanisms involve regulation of angiomotin, and cooperation of these mechanisms establishes cell position-dependent activation of Hippo signaling. At the 16-cell stage, however, asymmetric cell division produces the initial differences in Hippo signaling. At this stage, cell polarity is controlled by both Par-aPKC-dependent and -independent mechanisms. All three historical models are explained by the different regulations and roles of Hippo signaling. Based on these findings, I would like to propose the model by which the differences in Hippo signaling among blastomeres is first produced by asymmetric cell division and then enhanced and stabilized by cell position-dependent mechanisms until their fates are fixed.

Pub.: 31 Dec '16, Pinned: 18 Sep '17