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Cited by 114Developmental Biology and Gene RegulationProtein Kinase Regulation and GTPase SignalingCellular Mechanics and Interactions

Rac1-Dependent Collective Cell Migration Is Required for Specification of the Anterior-Posterior Body Axis of the Mouse

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Migeotte, Isabelle, Omelchenko, Tatiana, Hall, Alan, Anderson, Kathryn V.·2010·PLoS Biology
DOI 10.1371/journal.pbio.1000442PMC PMC2914637
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Abstract

Cell migration and cell rearrangements are critical for establishment of the body plan of vertebrate embryos. The first step in organization of the body plan of the mouse embryo, specification of the anterior-posterior body axis, depends on migration of the anterior visceral endoderm from the distal tip of the embryo to a more proximal region overlying the future head. The anterior visceral endoderm (AVE) is a cluster of extra-embryonic cells that secretes inhibitors of the Wnt and Nodal pathways to inhibit posterior development. Because Rac proteins are crucial regulators of cell migration and mouse Rac1 mutants die early in development, we tested whether Rac1 plays a role in AVE migration. Here we show that Rac1 mutant embryos fail to specify an anterior-posterior axis and, instead, express posterior markers in a ring around the embryonic circumference. Cells that express the molecular markers of the AVE are properly specified in Rac1 mutants but remain at the distal tip of the embryo at the time when migration should take place. Using tissue specific deletions, we show that Rac1 acts autonomously within the visceral endoderm to promote cell migration. High-resolution imaging shows that the leading wild-type AVE cells extend long lamellar protrusions that span several cell diameters and are polarized in the direction of cell movement. These projections are tipped by filopodia-like structures that appear to sample the environment. Wild-type AVE cells display hallmarks of collective cell migration: they retain tight and adherens junctions as they migrate and exchange neighbors within the plane of the visceral endoderm epithelium. Analysis of mutant embryos shows that Rac1 is not required for intercellular signaling, survival, proliferation, or adhesion in the visceral endoderm but is necessary for the ability of visceral endoderm cells to extend projections, change shape, and exchange neighbors. The data show that Rac1-mediated epithelial migration of the AVE is a crucial step in the establishment of the mammalian body plan and suggest that Rac1 is essential for collective migration in mammalian tissues.

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  • Mice lacking other critical actin-regulatory genes such as Rac1 and the WAVE complex component Nap1 show similar developmental abnormalities, resulting in death during early embryogenesis; deletion of Rac1 and Nap1 causes death during gastrulation at E7.5 and E9, respectively.

    “Similar developmental abnormalities, resulting in death during early embryogenesis, have been observed in mice lacking other critical actin-regulatory genes such as Rac1 and the WAVE complex component Nap1. Deletion of these genes in the mouse cause death during gastrulation at E7.5 and E9, respectively.69, 70, 71”

    From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [70]

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Authors
Migeotte, I., Omelchenko, T., Hall, A., & Anderson, K. V.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Anderson, Kathryn V.
ORCID
Venue
PLoS Biology
Publisher
Public Library of Science (PLoS)
Published
2010-08-03
Volume
8
Issue
8
Pages
e1000442
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.1000442
PMC
PMC2914637
OpenAlex
W1987509690
Cited by
114
References
1
Citations by year
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FWCI
4.04
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (4r37hd035455-16, HD035455)
  • National Cancer Institute (P30CA, P30-CA-08748, CA08748, P30CA008748)
  • National Institute of General Medical Sciences (R01GM081435, GM081435)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD035455, R37­HD035455, HD035455)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
Rac1, collective cell migration, anterior visceral endoderm, mouse embryo, body plan formation, filopodia, adherens junctions, tight junctions
MeSH terms
Animals, Cell Movement, Embryo, Mammalian, Embryonic Induction, Endoderm, Neuropeptides, Viscera, Gene Expression Regulation, Developmental, Body Patterning, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Embryo Culture Techniques, Embryonic Development, Mice

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