Genesis of Epithelial Polarity in Early Mammalian Embryos

Volume 8, Issue 6, December 2023     |     PP. 159-181      |     PDF (618 K)    |     Pub. Date: November 6, 2023
DOI: 10.54647/biology180331    52 Downloads     140736 Views  


Xiang-Xi Mike Xu, Department of Radiation Oncology; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, United States
Elizabeth R. Smith, Department of Radiation Oncology; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, United States

Epithelial cells comprise the surface layers that cover tissues and organs, and by definition, exhibit an asymmetric surface domain and hence apical-basal polarity. The development of early mammalian embryos, from a fertilized oocyte to a blastocyst and implanted embryo, provides an excellent system to observe the formation and morphogenesis of several epithelia. From our studies of early mouse embryonic development and morphogenesis, we propose that there are at the least three distinct types of mechanisms for polarization of epithelial cells: the classical tight junction and Par complexes; cell autonomous polarity established by endocytosis; and the subtle polarization caused by the formation of an apical actin cap of adjacent cells. Here, we describe the understanding of the genesis of four embryonic epithelial structures, the trophectoderm, inner cell mass, primitive endoderm, and epiblast, and the genes that are critical for their epithelial polarity and associated morphogenesis.

blastocysts, early embryos, morphogenesis, cell sorting, embryonic stem cells, epithelial polarity.

Cite this paper
Xiang-Xi Mike Xu, Elizabeth R. Smith, Genesis of Epithelial Polarity in Early Mammalian Embryos , SCIREA Journal of Biology. Volume 8, Issue 6, December 2023 | PP. 159-181. 10.54647/biology180331


[ 1 ] Alarcon VB. Cell polarity regulator PARD6B is essential for trophectoderm formation in the preimplantation mouse embryo. Biol Reprod. 2010 Sep;83(3):347-58.
[ 2 ] Anani S, Bhat S, Honma-Yamanaka N, Krawchuk D, Yamanaka Y. Initiation of Hippo signaling is linked to polarity rather than to cell position in the pre-implantation mouse embryo. Development. 2014 Jul;141(14):2813-24.
[ 3 ] Bedzhov I, Zernicka-Goetz M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell 2014; 156:1032-1044.
[ 4 ] Bedzhov I, Zernicka-Goetz M. Cell death and morphogenesis during early mouse development: are they interconnected? Bioessays. 2015 Apr;37(4):372-8.
[ 5 ] Bessonnard S, De Mot L, Gonze D, Barriol M, Dennis C, Goldbeter A, Dupont G, Chazaud C. Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network. Development 2014; 141:3637-3648.
[ 6 ] Campanale JP, Sun TY, Montell DJ. Development and dynamics of cell polarity at a glance. J Cell Sci. 2017 Apr 1;130(7):1201-1207.
[ 7 ] Cai KQ, Capo-Chichi CD, Rula ME, Yang DH, Xu XX. Dynamic GATA6 expression in primitive endoderm formation and maturation in early mouse embryogenesis. Dev Dyn 2008; 237:2820-2829.
[ 8 ] Capo-Chichi CD, Rula ME, Smedberg JL, Vanderveer L, Parmacek MS, Morrisey EE, Godwin AK, Xu XX. Perception of differentiation cues by GATA factors in primitive endoderm lineage determination of mouse embryonic stem cells. Dev Biol 2005; 286:574-586.
[ 9 ] Capo-Chichi CD, Smedberg JL, Rula M, Nicolas E, Yeung AT, Adamo RF, Frolov A, Godwin AK, Xu XX. Alteration of Differentiation Potentials by Modulating GATA Transcription Factors in Murine Embryonic Stem Cells. Stem Cells Int. 2010; 2010:602068.
[ 10 ] Carracedo S, Sacher F, Brandes G, Braun U, Leitges M. Redundant role of protein kinase C delta and epsilon during mouse embryonic development. PLoS One. 2014 Aug 1;9(8):e103686.
[ 11 ] Chazaud C, Yamanaka Y. Lineage specification in the mouse preimplantation embryo. Development 2016; 143:1063-1074.
[ 12 ] Chazaud C, Yamanaka Y, Pawson T, Rossant J: Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell 2006; 10:615-624.
[ 13 ] Chen F, Ma L, Parrini MC, Mao X, Lopez M, Wu C, Marks PW, Davidson L, Kwiatkowski DJ, Kirchhausen T, Orkin SH, Rosen FS, Mayer BJ, Kirschner MW, Alt FW. Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability. Curr Biol. 2000 Jun 29;10(13):758-65.
[ 14 ] Chen J, Zhang M. The Par3/Par6/aPKC complex and epithelial cell polarity. Exp Cell Res. 2013 Jun 10;319(10):1357-64.
[ 15 ] Cheng AM, Saxton TM, Sakai R, Kulkarni S, Mbamalu G, Vogel W, Tortorice CG, Cardiff RD, Cross JC, Muller WJ, Pawson T. Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 1998; 95:793-803.
[ 16 ] Christodoulou N, Kyprianou C, Weberling A, Wang R, Cui G, Peng G, Jing N, Zernicka-Goetz M. Sequential formation and resolution of multiple rosettes drive embryo remodelling after implantation. Nat Cell Biol. 2018 Nov;20(11):1278-1289.
[ 17 ] Coucouvanis E, Martin GR. 1995. Signals for death and survival: a two-step mechanism for cavitation in the vertebrate embryo. Cell 83:279-287.
[ 18 ] Coucouvanis E, Martin GR. BMP signaling plays a role in visceral endoderm differentiation and cavitation in the early mouse embryo. Development 1999; 126:535-546.
[ 19 ] Dance AL, Miller M, Seragaki S, Aryal P, White B, Aschenbrenner L, Hasson T. Regulation of myosin-VI targeting to endocytic compartments. Traffic. 2004 Oct;5(10):798-813.
[ 20 ] Dard N, Le T, Maro B, Louvet-Vallée S. Inactivation of aPKClambda reveals a context dependent allocation of cell lineages in preimplantation mouse embryos. PLoS One. 2009 Sep 21;4(9):e7117.
[ 21 ] Eckert JJ, Fleming TP. Tight junction biogenesis during early development. Biochimica et Biophysica Acta (BBA) – Biomembranes. 2008; 778:717-728.
[ 22 ] Fässler R, Meyer M. 1995. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 9:1896–1908.
[ 23 ] Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M. Requirement of FGF-4 for postimplantation mouse development. Science 1995; 267:246-249.
[ 24 ] Forteza R, Wald FA, Mashukova A, Kozhekbaeva Z, Salas PJ. Par-complex aPKC and Par3 cross-talk with innate immunity NF-κB pathway in epithelial cells. Biol Open. 2013 Oct 8;2(11):1264-9.
[ 25 ] Forteza R, Figueroa Y, Mashukova A, Dulam V, Salas PJ. Conditional knockout of polarity complex (atypical) PKCι reveals an anti-inflammatory function mediated by NF-κB. Mol Biol Cell. 2016 Jul 15;27(14):2186-97.
[ 26 ] Frankenberg S, Gerbe F, Bessonnard S, Belville C, Pouchin P, Bardot O, Chazaud C. Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling. Dev Cell 2011; 21:1005-1013.
[ 27 ] Frankenberg SR, de Barros FR, Rossant J, Renfree MB. The mammalian blastocyst. Wiley Interdiscip Rev Dev Biol. 2016 Mar-Apr;5(2):210-32.
[ 28 ] Fujikura J, Yamato E, Yonemura S, Hosoda K, Masui S, Nakao K, Miyazaki J, Niwa H. Differentiation of embryonic stem cells is induced by GATA factors. Gene Dev 2002; 16:784-789.
[ 29 ] Furuta Y, Ilić D, Kanazawa S, Takeda N, Yamamoto T, Aizawa S. Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene. 1995 Nov 16;11(10):1989-95.
[ 30 ] Gardner RL. Cell allocation and lineage in the early mouse embryo. Ciba Found Symp 1989; 144:172-181; discussion 181-186, 208-211.
[ 31 ] Gardner RL. Origin and differentiation of extraembryonic tissues in the mouse. Int Rev Exp Pathol 1983; 24:63-133.
[ 32 ] Gardner RL. Investigation of cell lineage and differentiation in the extraembryonic endoderm of the mouse embryo. J Embryol Exp Morphol 1982; 68:175-198.
[ 33 ] Gerbe F, Cox B, Rossant J, Chazaud C. Dynamic expression of Lrp2 pathway members reveals progressive epithelial differentiation of primitive endoderm in mouse blastocyst. Dev Biol. 2008 Jan 15;313(2):594-602.
[ 34 ] Goldin SN, Papaioannou VE. Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm. Genesis 2003; 36:40-47.
[ 35 ] Greber B, Wu G, Bernemann C, Joo JY, Han DW, Ko K, Tapia N, Sabour D, Sterneckert J, Tesar P, Schöler HR. Conserved and divergent roles of FGF signaling in mouse epiblast stem cells and human embryonic stem cells. Cell Stem Cell. 2010 Mar 5;6(3):215-26.
[ 36 ] Hayashi S, Lewis P, Pevny L, McMahon AP. Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain. Mech Dev 2002; 119:S97-S101.
[ 37 ] Hermitte S, Chazaud C. Primitive endoderm differentiation: from specification to epithelium formation. Phil Tran Royal Soc of London Series B 2014; 369:1657.
[ 38 ] Hirose T, Karasawa M, Sugitani Y, Fujisawa M, Akimoto K, Ohno S, Noda T. PAR3 is essential for cyst-mediated epicardial development by establishing apical cortical domains. Development. 2006 Apr;133(7):1389-98.
[ 39 ] Joberty, G., Petersen, C., Gao, L., Macara, I. G. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nature Cell Biol. 2: 531-539, 2000.
[ 40 ] Johnson MH, McConnell JM. Lineage allocation and cell polarity during mouse embryogenesis. Semin Cell Dev Biol. 2004 Oct;15(5):583-97.
[ 41 ] Jones C, Hammer RE, Li WP, Cohen JC, Hobbs HH, Herz J. Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia. J Biol Chem. 2003 Aug 1;278(31):29024-30.
[ 42 ] Kang M, Piliszek A, Artus J, Hadjantonakis AK. FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse. Development 2013; 140:267-279.
[ 43 ] Kang M, Garg V, Hadjantonakis AK. Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2. Dev Cell. 2017 Jun 5;41(5):496-510.e5.
[ 44 ] Keramari M, Razavi J, Ingman KA, Patsch C, Edenhofer F, Ward CM, Kimber SJ: Sox2 is essential for formation of trophectoderm in the preimplantation embryo. PLoS One 2010; 5:e13952.
[ 45 ] Kim YS, Fan R, Kremer L, Kuempel-Rink N, Mildner K, Zeuschner D, Hekking L, Stehling M, Bedzhov I. Deciphering epiblast lumenogenesis reveals proamniotic cavity control of embryo growth and patterning. Sci Adv. 2021 Mar 10;7(11):eabe1640.
[ 46 ] Krawchuk D, Honma-Yamanaka N, Anani S, Yamanaka Y. FGF4 is a limiting factor controlling the proportions of primitive endoderm and epiblast in the ICM of the mouse blastocyst. Dev Biol 2013; 384:65-71.
[ 47 ] Korotkevich E, Niwayama R, Courtois A, Friese S, Berger N, Buchholz F, Hiiragi T. The Apical Domain Is Required and Sufficient for the First Lineage Segregation in the Mouse Embryo. Dev Cell. 2017 Feb 6;40(3):235-247.e7.
[ 48 ] Kuijk EW, van Tol LT, Van de Velde H, Wubbolts R, Welling M, Geijsen N, Roelen BA. The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos. Development 2012; 139:871-882.
[ 49 ] Lanner F, Rossant J. The role of FGF/Erk signaling in pluripotent cells. Development 2010; 137:3351-3360.
[ 50 ] Larue, L., Ohsugi, M., Hirchenhain, J. and Kemler, R. (1994). E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proc. Natl. Acad. Sci. USA 91, 8263-8267.
[ 51 ] Lau MT, Klausen C, Leung PC. E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression. Oncogene. 2011 Jun 16;30(24):2753-66.
[ 52 ] Leung CY, Zhu M, Zernicka-Goetz M. Polarity in Cell-Fate Acquisition in the Early Mouse Embryo. Curr Top Dev Biol. 2016;120:203-34.
[ 53 ] Leitges M, et al. (2001) Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol Cell 8:771-780.
[ 54 ] Li L, Sun L, Gao F, Jiang J, Yang Y, Li C, Gu J, Wei Z, Yang A, Lu R, Ma Y, Tang F, Kwon SW, Zhao Y, Li J, Jin Y. Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation. Proc Natl Acad Sci USA. 2010; 107:1402-7.
[ 55 ] Li S, Edgar D, Fässler R, Wadsworth W, Yurchenco PD. The role of laminin in embryonic cell polarization and tissue organization. Dev Cell. 2003 May;4(5):613-24.
[ 56 ] Lim HYG, Alvarez YD, Gasnier M, Wang Y, Tetlak P, Bissiere S, Wang H, Biro M, Plachta N. Keratins are asymmetrically inherited fate determinants in the mammalian embryo. Nature. 2020 Sep;585(7825):404-409.
[ 57 ] Lim HYG, Plachta N. Cytoskeletal control of early mammalian development. Nat Rev Mol Cell Biol. 2021 Apr 29. doi: 10.1038/s41580-021-00363-9.
[ 58 ] Lu CC, Brennan J, Robertson EJ. From fertilization to gastrulation: axis formation in the mouse embryo. Curr Opin Genet Dev 2001; 11:384-392.
[ 59 ] Mah IK, Soloff R, Izuhara AK, Lakeland DL, Wang C, Mariani FV. Prkci is required for a non-autonomous signal that coordinates cell polarity during cavitation. Dev Biol. 2016 Aug 1;416(1):82-97.
[ 60 ] Martin E, Girardello R, Dittmar G, Ludwig A. New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells. FEBS J. 2021 Jan 14.
[ 61 ] Maurer ME, Cooper JA. Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein. J Cell Sci. 2005 Nov 15;118(Pt 22):5345-55.
[ 62 ] Meng Y, Cai KQ, Moore R, Tao W, Tse JD, Smith ER, Xu XX. Pten facilitates epiblast epithelial polarization and proamniotic lumen formation in early mouse embryos. Dev Dyn. 2017;246(7):517-530.
[ 63 ] Meng Y, Moore R, Tao W, Smith ER, Tse JD, Caslini C, Xu XX. GATA6 phosphorylation by Erk1/2 propels exit from pluripotency and commitment to primitive endoderm. Dev Biol. 2018;436(1):55-65.
[ 64 ] Mihajlović AI, Bruce AW. The first cell-fate decision of mouse preimplantation embryo development: integrating cell position and polarity. Open Biol. 2017 Nov;7(11). pii: 170210.
[ 65 ] Molotkov A, Mazot P, Brewer JR, Cinalli RM, Soriano P. Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency. Dev Cell. 2017 Jun 5;41(5):511-526.e4.
[ 66 ] Moore R, Cai KQ, Escudero DO, Xu XX. Cell adhesive affinity does not dictate primitive endoderm segregation and positioning during murine embryoid body formation. Genesis 2009; 47:579-589.
[ 67 ] Moore R, Cai KQ, Tao W, Smith ER, Xu XX. Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues. BMC Dev Biol 2013; 13:39.
[ 68 ] Moore R, Tao W, Smith ER, Xu XX. The primitive endoderm segregates from the epiblast in beta1 integrin-deficient early mouse embryos. Mol Cell Biol 2014; 34:560-572.
[ 69 ] Moore R, Tao W, Meng Y, Smith ER, Xu XX. Cell adhesion and sorting in embryoid bodies derived from N- or E-cadherin deficient murine embryonic stem cells. Biol Open. 2014 Feb 15;3(2):121-8.
[ 70 ] Morris SM, Arden SD, Roberts RC, Kendrick-Jones J, Cooper JA, Luzio JP, Buss F. Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton. Traffic. 2002 May;3(5):331-41.
[ 71 ] Morris SA, Teo RT, Li H, Robson P, Glover DM, Zernicka-Goetz M. Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo. Proc Natl Acad Sci USA 2010; 107:6364-6369.
[ 72 ] Morrisey EE, Ip HS, Lu MM, Parmacek MS. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev Biol 1996; 177:309-322.
[ 73 ] Morrisey EE, Tang Z, Sigrist K, Lu MM, Jiang F, Ip HS, Parmacek MS. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev 1998; 12:3579-3590.
[ 74 ] Morrisey EE, Musco S, Chen MY, Lu MM, Leiden JM, Parmacek MS. The gene encoding the mitogen-responsive phosphoprotein Dab2 is differentially regulated by GATA-6 and GATA-4 in the visceral endoderm. J Biol Chem 2000; 275:19949-19954.
[ 75 ] Nakai-Futatsugi Y, Niwa H. Epiblast and primitive endoderm differentiation: fragile specification ensures stable commitment. Cell Stem Cell 2015; 16:346-347.
[ 76 ] Nance J. Getting to know your neighbor: cell polarization in early embryos. J Cell Biol. 2014 Sep 29;206(7):823-32.
[ 77 ] Niakan KK, Schrode N, Cho LT, Hadjantonakis AK. Derivation of extraembryonic endoderm stem (XEN) cells from mouse embryos and embryonic stem cells. Nature protocols 2013; 8:1028-1041.
[ 78 ] Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Scholer H, Smith A. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 1998; 95:379-391.
[ 79 ] Nichols J, Silva J, Roode M, Smith A. Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 2009; 136:3215-3222.
[ 80 ] Ohnishi, Y. et al. Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages. Nature cell biology 16, 27-37, (2014).
[ 81 ] Ohsugi M, Larue L, Schwarz H, Kemler R. Cell-junctional and cytoskeletal organization in mouse blastocysts lacking E-cadherin. Dev Biol. 1997 May 15;185(2):261-71.
[ 82 ] Phua DC, Xu J, Ali SM, Boey A, Gounko NV, Hunziker W. ZO-1 and ZO-2 are required for extra-embryonic endoderm integrity, primitive ectoderm survival and normal cavitation in embryoid bodies derived from mouse embryonic stem cells. PLoS One. 2014 Jun 6;9(6):e99532.
[ 83 ] Plusa B, Piliszek A, Frankenberg S, Artus J, Hadjantonakis AK. Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development 2008; 135:3081-3091.
[ 84 ] Pöschl E, Schlötzer-Schrehardt U, Brachvogel B, Saito K, Ninomiya Y, Mayer U. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development. 2004 Apr;131(7):1619-28.
[ 85 ] Radice GL, Rayburn H, Matsunami H, Knudsen KA, Takeichi M, Hynes RO. Developmental defects in mouse embryos lacking N-cadherin. Dev Biol. 1997 Jan 1;181(1):64-78.
[ 86 ] Rappolee DA, Basilico C, Patel Y, Werb Z. Expression and function of FGF-4 in peri-implantation development in mouse embryos. Development 1994; 120:2259-2269.
[ 87 ] Rossant J, Chazaud C, Yamanaka Y. Lineage allocation and asymmetries in the early mouse embryo. Phil Tran Royal Soc of London Series B Biological Sciences 2003; 358:1341-1348; discussion 1349.
[ 88 ] Rossant J. Lineage development and polar asymmetries in the peri-implantation mouse blastocyst. Semin Cell Dev Biol 2004; 15:573-581.
[ 89 ] Rossant J. Mouse and human blastocyst-derived stem cells: vive les differences. Development. 2015 Jan 1;142(1):9-12.
[ 90 ] Rossant J, Tam PP. Emerging asymmetry and embryonic patterning in early mouse development. Dev Cell 2004; 7:155–164.
[ 91 ] Rossant J, Tam PP. New Insights into Early Human Development: Lessons for Stem Cell Derivation and Differentiation. Cell Stem Cell 2017; 20:18-28.
[ 92 ] Rula ME, Cai KQ, Moore R, Yang DH, Staub CM, Capo-Chichi CD, Jablonski SA, Howe PH, Smith ER, Xu XX. Cell autonomous sorting and surface positioning in the formation of primitive endoderm in embryoid bodies. Genesis 2007; 45:327-338.
[ 93 ] Saiz N, Grabarek JB, Sabherwal N, Papalopulu N, Plusa B. Atypical protein kinase C couples cell sorting with primitive endoderm maturation in the mouse blastocyst. Development. 2013 Nov;140(21):4311-22.
[ 94 ] Salas PJ, Misek DE, Vega-Salas DE, Gundersen D, Cereijido M, Rodriguez-Boulan E. Microtubules and actin filaments are not critically involved in the biogenesis of epithelial cell surface polarity. J Cell Biol. 1986 May;102(5):1853-67.
[ 95 ] Salas PJ, Rodriguez ML, Viciana AL, Vega-Salas DE, Hauri HP. The apical submembrane cytoskeleton participates in the organization of the apical pole in epithelial cells. J Cell Biol. 1997 Apr 21;137(2):359-75.
[ 96 ] Salas PJ, Vega-Salas DE, Hochman J, Rodriguez-Boulan E, Edidin M. Selective anchoring in the specific plasma membrane domain: a role in epithelial cell polarity. J Cell Biol. 1988 Dec;107(6 Pt 1):2363-76.
[ 97 ] Schrode N, Xenopoulos P, Piliszek A, Frankenberg S, Plusa B, Hadjantonakis AK. Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo. Genesis 2013; 51:219-233.
[ 98 ] Schröter C, Rué P, Mackenzie JP, Martinez-Arias A. FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells. Development 2015; 142:4205-4216.
[ 99 ] Sengupta A, Duran A, Ishikawa E, Florian MC, Dunn SK, Ficker AM, Leitges M, Geiger H, Diaz-Meco M, Moscat J, Cancelas JA. Atypical protein kinase C (aPKCzeta and aPKClambda) is dispensable for mammalian hematopoietic stem cell activity and blood formation. Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9957-62. Erratum in: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12185.
[ 100 ] Shahbazi MN, Jedrusik A, Vuoristo S, Recher G, Hupalowska A, Bolton V, Fogarty NNM, Campbell A, Devito L, Ilic D, Khalaf Y, Niakan KK, Fishel S, Zernicka-Goetz M. Self-organization of the human embryo in the absence of maternal tissues. Nat Cell Biol. 2016 Jun;18(6):700-708.
[ 101 ] Shahbazi MN, Scialdone A, Skorupska N, Weberling A, Recher G, Zhu M, Jedrusik A, Devito LG, Noli L, Macaulay IC, Buecker C, Khalaf Y, Ilic D, Voet T, Marioni JC, Zernicka-Goetz M. Pluripotent state transitions coordinate morphogenesis in mouse and human embryos. Nature. 2017 Dec 14;552(7684):239-243.
[ 102 ] Ryan AQ, Chan CJ, Graner F, Hiiragi T. Lumen Expansion Facilitates Epiblast-Primitive Endoderm Fate Specification during Mouse Blastocyst Formation. Dev Cell. 2019 Dec 16;51(6):684-697.e4.
[ 103 ] Sheth B, Nowak RL, Anderson R, Kwong WY, Papenbrock T, Fleming TP. Tight junction protein ZO-2 expression and relative function of ZO-1 and ZO-2 during mouse blastocyst formation. Exp Cell Res. 2008 Nov 1;314(18):3356-68.
[ 104 ] Smith ER, Capo-chichi CD, He J, Smedberg JL, Yang DH, Prowse AH, Godwin AK, Hamilton TC, Xu XX. Disabled-2 mediates c-Fos suppression and the cell growth regulatory activity of retinoic acid in embryonic carcinoma cells. J Biol Chem 2001; 276:47303-47310.
[ 105 ] Smith ER, Smedberg JL, Rula ME, Xu XX. Regulation of Ras-MAPK pathway mitogenic activity by restricting nuclear entry of activated MAPK in endoderm differentiation of embryonic carcinoma and stem cells. J Cell Biol. 2004 Mar 1;164(5):689-99.
[ 106 ] Smith ER, Meng Y, Moore R, Tse JD, Xu AG, Xu XX. Nuclear envelope structural proteins facilitate nuclear shape changes accompanying embryonic differentiation and fidelity of gene expression. BMC Cell Biol. 2017; 18(1):8.
[ 107 ] Steinberg MS. Differential adhesion in morphogenesis: a modern view. Curr Opin Genet Dev 2007; 17:281-286.
[ 108 ] STEINBERG MS. Reconstruction of tissues by dissociated cells. Some morphogenetic tissue movements and the sorting out of embryonic cells may have a common explanation. Science. 1963 Aug 2;141(3579):401-8.
[ 109 ] Steinberg MS, Gilbert SF. Townes and Holtfreter (1955): directed movements and selective adhesion of embryonic amphibian cells. J Exp Zool A Comp Exp Biol 2004; 301:701-706.
[ 110 ] Stephenson RO, Yamanaka Y, Rossant J. 2010. Disorganized epithelial polarity and excess trophectoderm cell fate in preimplantation embryos lacking E-cadherin. Development 137, 3383–3391.
[ 111 ] Stephenson RO, Rossant J, Tam PP. Intercellular interactions, position, and polarity in establishing blastocyst cell lineages and embryonic axes. Cold Spring Harb Perspect Biol. 2012 Nov 1;4(11).
[ 112 ] Stephens LE, Sutherland AE, Klimanskaya IV, Andrieux A, Meneses J, Pedersen RA, Damsky CH. 1995. Deletion of beta 1 integrins in mice results in inner cell mass failure and peri-implantation lethality. Genes Dev. 9:1883–1895.
[ 113 ] Sugihara K, Nakatsuji N, Nakamura K, Nakao K, Hashimoto R, Otani H, Sakagami H, Kondo H, Nozawa S, Aiba A, Katsuki M. Rac1 is required for the formation of three germ layers during gastrulation. Oncogene. 1998 Dec 31;17(26):3427-33.
[ 114 ] Tam PP, Loebel DA. Gene function in mouse embryogenesis: get set for gastrulation. Nat Rev Genet 2007; 8:368-381.
[ 115 ] Tao W, Moore R, Smith ER, Xu XX. Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice. Front Cell Dev Biol. 2016 Nov 25;4:129.
[ 116 ] Tao W, Moore R, Meng Y, Smith ER, Xu XX. Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol. J Lipid Res. 2016 May;57(5):809-17.
[ 117 ] Tse JD, Moore R, Meng Y, Tao W, Smith ER, Xu XX. Dynamic conversion of cell sorting patterns in aggregates of embryonic stem cells with differential adhesive affinity. BMC Dev Biol. 2021 Jan 6;21(1):2.
[ 118 ] Vallier L, Touboul T, Chng Z, Brimpari M, Hannan N, Millan E, Smithers LE, Trotter M, Rugg-Gunn P, Weber A, Pedersen RA. Early cell fate decisions of human embryonic stem cells and mouse epiblast stem cells are controlled by the same signalling pathways. PLoS One. 2009 Jun 30;4(6):e6082.
[ 119 ] Vega-Salas DE, Salas PJ, Gundersen D, Rodriguez-Boulan E. Formation of the apical pole of epithelial (Madin-Darby canine kidney) cells: polarity of an apical protein is independent of tight junctions while segregation of a basolateral marker requires cell-cell interactions. J Cell Biol. 1987 Apr;104(4):905-16.
[ 120 ] Wang Y, Smedberg JL, Cai KQ, Capo-Chichi DC, Xu XX: Ectopic expression of GATA6 bypasses requirement for Grb2 in primitive endoderm formation. Dev Dyn 2011; 240:566-576.
[ 121 ] Whiteman EL, Fan S, Harder JL, Walton KD, Liu CJ, Soofi A, Fogg VC, Hershenson MB, Dressler GR, Deutsch GH, Gumucio DL, Margolis B. Crumbs3 is essential for proper epithelial development and viability. Mol Cell Biol. 2014 Jan;34(1):43-56.
[ 122 ] Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, Ray P, Whitaker JW, Tian S, Hawkins RD, Leung D, Yang H, Wang T, Lee AY, Swanson SA, Zhang J, Zhu Y, Kim A, Nery JR, Urich MA, Kuan S, Yen CA, Klugman S, Yu P, Suknuntha K, Propson NE, Chen H, Edsall LE, Wagner U, Li Y, Ye Z, Kulkarni A, Xuan Z, Chung WY, Chi NC, Antosiewicz-Bourget JE, Slukvin I, Stewart R, Zhang MQ, Wang W, Thomson JA, Ecker JR, Ren B. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell. 2013 May 23;153(5):1134-48.
[ 123 ] Xu J, Kausalya PJ, Phua DC, Ali SM, Hossain Z, Hunziker W. Early embryonic lethality of mice lacking ZO-2, but Not ZO-3, reveals critical and nonredundant roles for individual zonula occludens proteins in mammalian development. Mol Cell Biol. 2008 Mar;28(5):1669-78.
[ 124 ] Xu XX, Yang W, Jackowski S, Rock CO. Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. J Biol Chem 1995; 270:14184-14191.
[ 125 ] Yamanaka Y, Lanner F, Rossant J. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 2010; 137:715-724.
[ 126 ] Yano T, Kanoh H, Tamura A, Tsukita S. Apical cytoskeletons and junctional complexes as a combined system in epithelial cell sheets. Ann N Y Acad Sci. 2017;1405(1):32-43.
[ 127 ] Yang DH, Smith ER, Roland IH, Sheng Z, He J, Martin WD, Hamilton TC, Lambeth JD, Xu XX. Disabled-2 is essential for endodermal cell positioning and structure formation during early extraembryonic development. Dev Biol 2002; 251:27-44.
[ 128 ] Yang DH, Cai KQ, Roland IH, Smith ER, Xu XX. Disabled-2 is an epithelial surface positioning gene. J Biol Chem 2007; 282:13114-13122.
[ 129 ] Yang DH, Smith ER, Cai KQ, Xu XX. C-Fos elimination compensates for disabled-2 requirement in mouse extraembryonic endoderm development. Dev Dyn 2009; 238:514-523.
[ 130 ] Yang DH, Cai KQ, Roland IH, Smith ER, Xu XX. Disabled-2 is an epithelial surface positioning gene. J Biol Chem. 2007 Apr 27;282(17):13114-22.
[ 131 ] Yang JQ, Leitges M, Duran A, Diaz-Meco MT, Moscat J. Loss of PKC lambda/iota impairs Th2 establishment and allergic airway inflammation in vivo. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1099-104.
[ 132 ] Yano T, Kanoh H, Tamura A, Tsukita S. Apical cytoskeletons and junctional complexes as a combined system in epithelial cell sheets. Ann N Y Acad Sci. 2017 Oct;1405(1):32-43.
[ 133 ] Zenker J, White MD, Gasnier M, Alvarez YD, Lim HYG, Bissiere S, Biro M, Plachta N. Expanding Actin Rings Zipper the Mouse Embryo for Blastocyst Formation. Cell. 2018 Apr 19;173(3):776-791.e17.
[ 134 ] Zhang HT, Hiiragi T. Symmetry Breaking in the Mammalian Embryo. Annu Rev Cell Dev Biol. 2018 Oct 6;34:405-426.
[ 135 ] Zhu M, Leung CY, Shahbazi MN, Zernicka-Goetz M. Actomyosin polarisation through PLC-PKC triggers symmetry breaking of the mouse embryo. Nat Commun. 2017 Oct 13;8(1):921.
[ 136 ] Zhu M, Cornwall-Scoones J, Wang P, Handford CE, Na J, Thomson M, Zernicka-Goetz M. Developmental clock and mechanism of de novo polarization of the mouse embryo. Science. 2020 Dec 11;370(6522):eabd2703.