E-カドヘリンはコンパクションに必要ということを阻害抗体で示した論文がある一方で、Ｅ-カドヘリンは内部細胞塊でのHIPPOキナーゼの活性化に必要という論文もあるようです。結局、E-カドヘリンは外側と内側のどっちの細胞で必要とされているのかということに関して矛盾してはいないのでしょうか。ちょっと混乱させられたのでPerplexityに訊いてみました。

質問　Strange enough, E-Cadherin acts during compaction. How you can consolidate the two facts: E-cadherin is nessary compaction in the outer cells, whereas E-cadherin is necessary for HIPPO activation in inner cells?

Perplexityの回答

Based on the search results and the information provided, we can consolidate the seemingly contradictory roles of E-cadherin in outer and inner cells during early embryo development as follows:

Role in outer cells during compaction:

E-cadherin is crucial for the compaction process in outer cells of the early embryo. It mediates cell-cell adhesion, which is essential for the morphological changes that occur during compaction.

1. Expression of e-cadherin in early mouse embryo development　Vet Hekim Der Derg 91 (1): 9-14, 2020　https://dergipark.org.tr/tr/download/article-file/925118
2. Cell adhesion in the preimplantation mammalian embryo and its role in trophectoderm differentiation and blastocyst morphogenesis　Front Biosci . 2001 Aug 1:6:D1000-7. doi: 10.2741/fleming. https://pubmed.ncbi.nlm.nih.gov/11487467/

E-cadherin localizes to cell-cell contact regions in outer cells, helping to establish the initial polarization of these cells.

1. PLoS One. 2019; 14(2): e0212109. Published online 2019 Feb 8. doi: 10.1371/journal.pone.0212109 PMCID: PMC6368326 PMID: 30735538 No evidence of involvement of E-cadherin in cell fate specification or the segregation of Epi and PrE in mouse blastocysts
2. Overview of junctional complexes during mammalian early embryonic development　Front. Endocrinol., 20 April 2023 Sec. Experimental Endocrinology Volume 14 – 2023 | https://doi.org/10.3389/fendo.2023.1150017

Role in inner cells and Hippo pathway activation:

In inner cells, E-cadherin plays a different role. It is involved in activating the Hippo signaling pathway, which is crucial for cell fate determination.

1. Mol Hum Reprod. 2016 Oct; 22(10): 691–703. Published online 2016 Oct 5. doi: 10.1093/molehr/gav068 PMCID: PMC5062000 PMID: 26660321 Polarity and cell division orientation in the cleavage embryo: from worm to human

The extensive cell-cell contacts mediated by E-cadherin in inner cells lead to the activation of Hippo pathway kinases.

1. Front. Endocrinol., 20 April 2023 Sec. Experimental Endocrinology Volume 14 – 2023 | https://doi.org/10.3389/fendo.2023.1150017 Overview of junctional complexes during mammalian early embryonic development

To consolidate these two facts, we can understand that:

a) E-cadherin’s function is context-dependent: Its role differs based on the cell’s position within the embryo (outer vs. inner).

b) Differential distribution: In outer cells, E-cadherin is redistributed during compaction, becoming concentrated at cell-cell contact sites but removed from the apical membrane domain. In inner cells, E-cadherin is more evenly distributed along the cell membrane.

c) Interaction with other factors: E-cadherin cooperates with other molecules like angiomotin (Amot) and the Par-aPKC system to establish polarity in outer cells and activate Hippo signaling in inner cells.

1. The E-cadherin/AmotL2 complex organizes actin filaments required for epithelial hexagonal packing and blastocyst hatching Scientific Reports volume 7, Article number: 9540 (2017). “and mammalian trophectoderm in vivo. We show that amotL2 is a component of the E-cadherin complex that is essential for the formation of radial actin filaments. Functionally, depletion of amotL2 and subsequent loss of radial actin fibers resulted in stalled hatching of mouse and human embryos from the zona pellucida.” https://www.nature.com/articles/s41598-017-10102-w AmotL2 (angiomotin-like 2) forms a complex with E-cadherin. This complex associates with radial actin filaments connecting cells over multiple layers. The paper shows that AmotL2 is part of the E-cadherin junctional protein complex. Co-immunoprecipitation analysis demonstrated that AmotL2 was directly or indirectly bound to E-cadherin as well as α and β-catenin.

d) Mechanical forces: The different mechanical environments of outer and inner cells may influence how E-cadherin-mediated adhesion translates into signaling outcomes.

1. Dual role of E-cadherin in cancer cells　Tissue Barriers Volume 10, 2022 – Issue 4 Submit an article Journal　https://www.tandfonline.com/doi/full/10.1080/21688370.2021.2005420

e) Temporal aspects: E-cadherin’s role evolves as development progresses. It first mediates compaction, then contributes to establishing and maintaining the distinct fates of outer (trophectoderm) and inner (inner cell mass) cells.

1. Gene replacement reveals a specific role for E-cadherin in the formation of a functional trophectoderm　01 January 2007  Development　https://journals.biologists.com/dev/article/134/1/31/52730/Gene-replacement-reveals-a-specific-role-for-E
2. https://embryology.med.unsw.edu.au/embryology/index.php?title=Morula_Development

In summary, E-cadherin plays a dual role: it is necessary for compaction in outer cells while also being crucial for Hippo pathway activation in inner cells. This dual function is achieved through differential localization, interaction with other proteins, and the distinct microenvironments of outer and inner cells in the early embryo.