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Keratins as Cell Fate Determinants in the Very Early Mammalian Embryo

Review of “Keratins are asymmetrically inherited fate determinants in the mammalian embryo” from Nature by Stuart P. Atkinson

The ‘cell polarity’ model of the first lineage specification steps that occur during mammalian development, which generates the pluripotent inner cell mass and the outer trophectoderm that forms the placenta, proposes that the asymmetric inheritance of specific components during cell division specifies distinct cell fates [1]. 

In the search for the polarized components that function as asymmetrically inherited fate determinants during mammalian development, researchers from the laboratory of Nicolas Plachta (ASTAR, Singapore & University of Pennsylvania, Philadelphia, PA, USA) turned to the study of keratins, given that they are the primary cytoplasmic intermediate filaments expressed during preimplantation development [2-4], and that keratin knockouts display, among other effects, lethality after implantation [5-7]. In the team’s recent Nature study [8], Lim et al. now provide evidence that differential keratin regulation during early mouse embryo development controls the asymmetrically inherited determination of cell fate.

Through immunofluorescence-based assays, the authors first noted that keratin proteins, and not F-actin or microtubules, displayed a prominent cell-to-cell variability at the eight-cell mouse embryo stage. At the blastocyst stage, this heterogeneity manifested itself as a dense network of keratin in the trophectoderm and the absence of any keratin expression within the inner cell mass. Live-embryo imaging using fluorescently labeled keratin mRNA demonstrated the assembly of keratin filaments only at the apical region of cells during interphase, which drove the asymmetrical inheritance of keratin filaments in the outer daughter cells will form the trophectoderm during cell division. Meanwhile, the daughter cells lacking inherited keratin became internalized and take on an inner cell mass fate. Additionally, the authors also discovered that keratins aided the specification of the first trophectoderm cells of the embryo by supporting the YAP1 (yes-associated protein 1)-dependent expression of Homeobox protein CDX-2 while also providing mechanical support for blastocyst morphogenesis.

Fascinatingly, the authors next provided evidence that differences in the activity of the BRG1-associated factor (BAF) chromatin-remodeling complex, which promotes trophectoderm differentiation and is negatively regulated by the histone methyltransferase CARM1 that biases inner cell mass fate [9, 10], trigger the differential expression of keratins and hence the dictation of trophectodermal fate at the eight-cell embryo stage. The delineation of this mechanism suggests that knowledge regarding BAF activity in blastomeres will allow the prediction of their future fate.

Finally, the authors also note a comparable cell-to-cell variability and localization of keratins in the human embryo, thereby suggesting that the asymmetric inheritance of keratins represents a conserved lineage specification mechanism that functions during early mammalian development.

Overall, the authors provide evidence for how cell heterogeneities in the very early embryo influence fate decisions via the differential expression of keratin, thereby identifying a crucial role for intermediate filaments in mouse, and perhaps human, development.

For more on how keratins function as cell fate determinants in the mammalian embryo, stay tuned to the Stem Cells Portal!


References

  1. Johnson MH and Ziomek CA, The foundation of two distinct cell lineages within the mouse morula. Cell 1981;24:71-80.
  2. Jackson BW, Grund C, Schmid E, et al., Formation of Cytoskeletal Elements During Mouse Embryogenesis: Intermediate Filaments of the Cytokeratin Type and Desmosomes in Preimplantation Embryos. Differentiation 1980;17:161-179.
  3. Paulin D, Babinet C, Weber K, et al., Antibodies as probes of cellular differentiation and cytoskeletal organization in the mouse blastocyst. Experimental Cell Research 1980;130:297-304.
  4. Oshima RG, Howe WE, Klier FG, et al., Intermediate filament protein synthesis in preimplantation murine embryos. Developmental Biology 1983;99:447-455.
  5. Baribault H, Price J, Miyai K, et al., Mid-gestational lethality in mice lacking keratin 8. Genes & Development 1993;7:1191-1202.
  6. Tamai Y, Ishikawa T-o, Bösl MR, et al., Cytokeratins 8 and 19 in the Mouse Placental Development. Journal of Cell Biology 2000;151:563-572.
  7. Hesse M, Franz T, Tamai Y, et al., Targeted deletion of keratins 18 and 19 leads to trophoblast fragility and early embryonic lethality. The EMBO Journal 2000;19:5060-5070.
  8. Lim HYG, Alvarez YD, Gasnier M, et al., Keratins are asymmetrically inherited fate determinants in the mammalian embryo. Nature 2020;585:404-409.
  9. Panamarova M, Cox A, Wicher KB, et al., The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo. Development 2016;143:1271.
  10. Wang L, Zhao Z, Meyer Mark B, et al., CARM1 Methylates Chromatin Remodeling Factor BAF155 to Enhance Tumor Progression and Metastasis. Cancer Cell 2014;25:21-36.