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First published online June 23, 2005
doi: 10.1242/10.1242/jcs.02422
Research Article |
1 Department of Pathology and Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
2 Max Planck Institute of Biochemistry, Department of Molecular Medicine, 82152 Martinsried, Germany
3 Institute of Molecular Pathology, University of Copenhagen, 2100 Copenhagen, Denmark
* Author for correspondence (e-mail: faessler{at}biochem.mpg.de)
Accepted 6 April 2005
PINCH1 is composed of 5 LIM domains, binds integrin-linked kinase (ILK) and locates to integrin-mediated adhesion sites. In order to investigate PINCH1 function we generated mice and embryonic stem (ES) cell-derived embryoid bodies (EBs) lacking the PINCH1 gene. Similar to mice lacking ß1 integrin or Ilk, loss of PINCH1 arrested development at the peri-implantation stage. In contrast to ß1 integrin or Ilk mutants, however, disruption of the PINCH1 gene produced implantation chambers with visible cell clumps even at embryonic day 9.5. In order to define the phenotype leading to the peri-implantation lethality we made PINCH1-null EBs and found similar but also additional defects not observed in ß1 integrin or Ilk mutant EBs. The similarities included abnormal epiblast polarity, impaired cavitation and detachment of endoderm and epiblast from basement membranes. Additional defects, which were not observed in ß1 integrin- or ILK-deficient mice or EBs, included abnormal cell-cell adhesion of endoderm and epiblast as well as the presence of apoptotic cells in the endodermal cell layer. Although ILK and PINCH1 were shown to be involved in the phosphorylation of serine-473 of PKB/Akt, immunostaining with specific antibodies revealed no apparent alteration of PKB/Akt phosphorylation in PINCH1-deficient EBs. Altogether these data demonstrate an important role of PINCH1 for integrin function, actin organization, cell-cell adhesion and endodermal cell survival during the implanting of mouse embryos.
Key words: PINCH (LIMS1), ILK, Integrin, Adhesion, Implantation, PKB/Akt
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