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PMID: 19056886 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation.

Genes & development ·Vol. 22 ·No. 23 ·2008-12-01 ·Pages 3349-62

Egea J, Erlacher C, Montanez E, Burtscher I, Yamagishi S, Hess M, Hampel F, Sanchez R, Rodriguez-Manzaneque MT, Bösl MR, Fässler R, Lickert H, Klein R

Abstract

During early mouse development, the anterior visceral endoderm (AVE) secretes inhibitor and activator signals that are essential for establishing the anterior-posterior (AP) axis of the embryo and for restricting mesoderm formation to the posterior epiblast in the primitive streak (PS) region. Here we show that AVE cells have an additional morphogenetic function. These cells express the transmembrane protein FLRT3. Genetic ablation of FLRT3 did not affect the signaling functions of the AVE according to the normal expression pattern of Nodal and Wnt and the establishment of a proper AP patterning in the epiblast. However, FLRT3(-/-) embryos showed a highly disorganized basement membrane (BM) in the AVE region. Subsequently, adjacent anterior epiblast cells displayed an epithelial-to-mesenchymal transition (EMT)-like process characterized by the loss of cell polarity, cell ingression, and the up-regulation of the EMT and the mesodermal marker genes Eomes, Brachyury/T, and FGF8. These results suggest that the AVE acts as a morphogenetic boundary to prevent EMT and mesoderm induction in the anterior epiblast by maintaining the integrity of the BM. We propose that this novel function cooperates with the signaling activities of the AVE to restrict EMT and mesoderm induction to the posterior epiblast.

MeSH Terms
Animals Basement Membrane/pathology,physiology Body Patterning Cell Differentiation/genetics Cell Movement Embryonic Development Embryonic Induction Endoderm/physiology Gene Expression Regulation, Developmental Membrane Glycoproteins/genetics,physiology Mesoderm/physiology Mice Mice, Knockout Morphogenesis Signal Transduction
Chemicals
FLRT3 protein, mouse Membrane Glycoproteins
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Egea Joaquim
Department of Molecular Neurobiology, Max-Planck Institute of Neurobiology, 82152 Martinsried, Germany. jegea@neuro.mpg.de
Erlacher Christian
Montanez Eloi
Burtscher Ingo
Yamagishi Satoru
Hess Martin
Hampel Falko
Sanchez Rodrigo
Rodriguez-Manzaneque Maria Teresa
Bösl Michael R
Fässler Reinhard
Lickert Heiko
Klein Rüdiger
References (48)
48 references, click to expand
  1. A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo.
    EMBO J. 1993 Jul;12(7):2735-47 PMID: 8101484
  2. A role for fibronectin-leucine-rich transmembrane cell-surface proteins in homotypic cell adhesion.
    EMBO Rep. 2006 Mar;7(3):283-90 PMID: 16440004
  3. The establishment of a somitomeric pattern in the mesoderm of the gastrulating mouse embryo.
    Am J Anat. 1982 Jul;164(3):209-25 PMID: 7124653
  4. BRCT domain-containing protein PTIP is essential for progression through mitosis.
    Mol Cell Biol. 2003 Mar;23(5):1666-73 PMID: 12588986
  5. Reconciling different models of forebrain induction and patterning: a dual role for the hypoblast.
    Development. 2000 Sep;127(17):3839-54 PMID: 10934028
  6. Axis specification and morphogenesis in the mouse embryo require Nap1, a regulator of WAVE-mediated actin branching.
    Development. 2006 Aug;133(16):3075-83 PMID: 16831833
  7. Ventral closure, headfold fusion and definitive endoderm migration defects in mouse embryos lacking the fibronectin leucine-rich transmembrane protein FLRT3.
    Dev Biol. 2008 Jun 1;318(1):184-93 PMID: 18448090
  8. Pivotal roles for eomesodermin during axis formation, epithelium-to-mesenchyme transition and endoderm specification in the mouse.
    Development. 2008 Feb;135(3):501-11 PMID: 18171685
  9. The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo.
    Development. 1995 Feb;121(2):439-51 PMID: 7768185
  10. Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages.
    Mech Dev. 1999 Aug;86(1-2):197-201 PMID: 10446282
  11. Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation.
    Oncogene. 2000 Aug 3;19(33):3750-6 PMID: 10949929
  12. The role of E-cadherin and integrins in mesoderm differentiation and migration at the mammalian primitive streak.
    Development. 1993 Jul;118(3):829-44 PMID: 7521282
  13. The role of laminin in embryonic cell polarization and tissue organization.
    Dev Cell. 2003 May;4(5):613-24 PMID: 12737798
  14. Regulation of EphA 4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function.
    Neuron. 2005 Aug 18;47(4):515-28 PMID: 16102535
  15. Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo.
    Nature. 2004 Mar 25;428(6981):387-92 PMID: 15004567
  16. Active cell migration drives the unilateral movements of the anterior visceral endoderm.
    Development. 2004 Mar;131(5):1157-64 PMID: 14973277
  17. TGF-beta signaling-mediated morphogenesis: modulation of cell adhesion via cadherin endocytosis.
    Genes Dev. 2007 Jul 15;21(14):1817-31 PMID: 17639085
  18. Molecular mechanisms of epithelial morphogenesis.
    Annu Rev Cell Dev Biol. 2002;18:463-93 PMID: 12142280
  19. Morphology of incipient mesoderm formation in the rabbit embryo: a light- and retrospective electron-microscopic study.
    Acta Anat (Basel). 1995;154(2):99-110 PMID: 8722509
  20. Identification of FLRT1, FLRT2, and FLRT3: a novel family of transmembrane leucine-rich repeat proteins.
    Genomics. 1999 Dec 15;62(3):417-26 PMID: 10644439
  21. The snail superfamily of zinc-finger transcription factors.
    Nat Rev Mol Cell Biol. 2002 Mar;3(3):155-66 PMID: 11994736
  22. Perlecan maintains the integrity of cartilage and some basement membranes.
    J Cell Biol. 1999 Nov 29;147(5):1109-22 PMID: 10579729
  23. Complex networks orchestrate epithelial-mesenchymal transitions.
    Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42 PMID: 16493418
  24. The hypoblast of the chick embryo positions the primitive streak by antagonizing nodal signaling.
    Dev Cell. 2002 Nov;3(5):735-44 PMID: 12431379
  25. Regulation of programmed cell death by basement membranes in embryonic development.
    J Cell Biol. 2000 Sep 4;150(5):1215-21 PMID: 10974008
  26. The anterior visceral endoderm-turning heads.
    Genesis. 2006 Nov;44(11):565-72 PMID: 17078044
  27. Mouse embryonic chimeras: tools for studying mammalian development.
    Development. 2003 Dec;130(25):6155-63 PMID: 14623817
  28. The amniote primitive streak is defined by epithelial cell intercalation before gastrulation.
    Nature. 2007 Oct 25;449(7165):1049-52 PMID: 17928866
  29. Emerging asymmetry and embryonic patterning in early mouse development.
    Dev Cell. 2004 Aug;7(2):155-64 PMID: 15296713
  30. The transmembrane protein XFLRT3 forms a complex with FGF receptors and promotes FGF signalling.
    Nat Cell Biol. 2004 Jan;6(1):38-44 PMID: 14688794
  31. Regulation of mesodermal differentiation of mouse embryonic stem cells by basement membranes.
    J Biol Chem. 2007 Oct 5;282(40):29701-11 PMID: 17690109
  32. Analysis of integrin functions in peri-implantation embryos, hematopoietic system, and skin.
    Methods Enzymol. 2007;426:239-89 PMID: 17697888
  33. Regulated expression of FLRT genes implies a functional role in the regulation of FGF signalling during mouse development.
    Dev Biol. 2006 Sep 1;297(1):14-25 PMID: 16872596
  34. RhoA and microtubule dynamics control cell-basement membrane interaction in EMT during gastrulation.
    Nat Cell Biol. 2008 Jul;10(7):765-75 PMID: 18552836
  35. Canonical Wnt signaling and its antagonist regulate anterior-posterior axis polarization by guiding cell migration in mouse visceral endoderm.
    Dev Cell. 2005 Nov;9(5):639-50 PMID: 16256739
  36. Regulation of the differentiation and behaviour of extra-embryonic endodermal cells by basement membranes.
    J Cell Sci. 2001 Mar;114(Pt 5):931-9 PMID: 11181176
  37. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak.
    Dev Cell. 2001 Jul;1(1):37-49 PMID: 11703922
  38. Fibroblast growth factor signaling and basement membrane assembly are connected during epithelial morphogenesis of the embryoid body.
    J Cell Biol. 2001 May 14;153(4):811-22 PMID: 11352941
  39. Transfer of extracellular matrix components between germ layers in chimaeric chicken-quail blastoderms.
    Cell Tissue Res. 1985;239(3):643-9 PMID: 3986883
  40. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo.
    Curr Biol. 1996 Nov 1;6(11):1487-96 PMID: 8939602
  41. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks.
    Dev Cell. 2002 Nov;3(5):745-56 PMID: 12431380
  42. Gene function in mouse embryogenesis: get set for gastrulation.
    Nat Rev Genet. 2007 May;8(5):368-81 PMID: 17387317
  43. A role for the hypoblast (AVE) in the initiation of neural induction, independent of its ability to position the primitive streak.
    Dev Biol. 2007 Jan 15;301(2):489-503 PMID: 17010966
  44. A scanning electron microscopic study of the surface morphology of visceral endoderm and ectoderm in postimplantation mouse embryos.
    J Electron Microsc (Tokyo). 1986;35(2):185-94 PMID: 3572293
  45. Axis development and early asymmetry in mammals.
    Cell. 1999 Jan 22;96(2):195-209 PMID: 9988215
  46. Distinct enhancer elements control Hex expression during gastrulation and early organogenesis.
    Dev Biol. 2001 Jun 15;234(2):304-16 PMID: 11397001
  47. From fertilization to gastrulation: axis formation in the mouse embryo.
    Curr Opin Genet Dev. 2001 Aug;11(4):384-92 PMID: 11448624
  48. What mouse mutants teach us about extracellular matrix function.
    Annu Rev Cell Dev Biol. 2006;22:591-621 PMID: 16824013
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.486708
Email
jegea@neuro.mpg.de
Published
2008-12-01
Pages
3349-62
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2600762
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.486708 PMC Full Text View journal details
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