Embryonic EMTs intercepted by p38
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654 NATURE CELL BIOLOGY VOLUME 8 | NUMBER 7 | JULY 2006 NEWS AND VIEWS In summary, this new study provides evi- dence for the specific presence of five RNAs in a centrosome fraction that has been cen- trifuged through the RNA-rich cytoplasm of the surf clam oocyte. This work should be applauded given the numerous techni- cal obstacles it faced. However, the incom- plete molecular characterization of the RNAs makes interpretation of the results difficult. Viewed in an epistemological and paradigmatic perspective, the progress made since the initial efforts 12–15 now seems like a series of tentative steps. The findings of Alliegro et al. may be a triplet of steps forward. ACKNOWLEDGEMENTS Joseph Gall (Carnegie Institution, Baltimore, MD) is gratefully acknowledged for kindly providing Fig. 1. The author wishes to pay tribute to his postdoctoral mentor, the late Elliott Robbins, an early investigator of centriole replication. 1. Wheatley, D. N. The Centriole: A Central Enigma of Cell Biology (Elsevier, Amsterdam and New York, 1982). 2. Wilson, E. B. The Cell in Development and Heredity 3 rd edn (Macmillan, New York, 1925). 3. Gall, J. G. in Centrosomes in Development and Disease (ed. Nigg, E. A.) 3–15 (Wiley-VCH, Weinheim, 2004). 4. Sluder, G. & Hinchcliffe, E. H. Biol. Cell 91, 413–427 (1999). 5. Marshall, W. F. & Rosenbaum, J. L. Curr. Topics Dev. Biol. 49, 187–205 (2000). 6. Alliegro, M. C., Alliegro, M. A. & Palazzo, R. E. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0602859103 (2006). 7. Klotz, C. et al. J. Cell Biol. 110, 405–415 (1990). 8. Reider, C. L. J. Cell Biol. 80, 1–9 (1979). 9. Went, H. A. J. Theoret. Biol. 68, 95–100 (1977). 10. Mello, C. C. & Conte, D., Jr Nature 431, 338– 342 (2004). 11. Han, J. W., Park, J. H., Kim, M. & Lee, J. J. Cell Biol. 137, 871–879 (1997). 12. Seaman, G. R. Exp. Cell Res. 21, 292–302 (1960). 13. Argetsinger, J. J. Cell Biol. 24, 154–157 (1965). 14. Hoffman, E. J. J. Cell Biol. 25, 217–228 (1965). 15. Dippel, R. V. J. Cell. Biol. 69, 622–637 (1976). 16. Gall, J.G. A Pictorial History. Views of the Cell (American Society for Cell Biology, Bethesda, 1996). 17. Vogel, J.M., Stearns, T., Reider, C.L. & Palazzo, R.E. J. Cell Biol. 137, 193–202 (1997). Embryonic EMTs intercepted by p38 During development of the early embryo, gastrulation results in the formation of the three germ layers. For this process to occur, mesoderm cells need to undergo a rapid epithelial to mesenchymal transition (EMT) and migrate away from the primitive streak. A key step in EMTs is the suppression of E-cadherin through FGF signalling and increased expression of the transcription factor Snail. Zohn et al. now introduce a new, independent signalling pathway that regulates EMT, which involves members of the MAPK cascade (Cell, 125, 957–969; 2006). The authors used an unbiased genetic screen to identify muta- tions that affect neural tube closure and gastrulation and stumbled on the mutant mouse line droopy eye (drey). drey encodes a p38- interacting protein (p38IP) and p38IP loss-of-function mutations cause severe development defects, including impaired migration of mesoderm cells from the primitive streak. The authors show that p38IP interacts with p38α in vitro and that this interaction is functionally relevant in vivo — embryonic tissues expressing p38IP truncation mutants that cannot bind p38 display impaired activation of p38 and its targets (see figure). To elucidate the function of p38IP, the authors first looked at the known EMT candidates. In mutant mesoderm cells that failed to migrate away from the primitive streak, although Snail was expressed and E-cadherin mRNA was downregulated as in wild-type cells, E-cadherin protein remained localized to adherens junctions. Thus, it seems that p38IP-mutant mesoderm can initiate EMTs, but cannot effi- ciently complete the task. The p38IP-mutant mesoderm cells that failed to migrate in the embryo also failed to migrate when explanted and migration was rescued by blocking E-cadherin function. Furthermore, p38 activity was also required for E-cadherin downregulation and EMT, but not for cell migration per se. Is the p38IP–p38 pathway also under the control of FGF signal- ling? Fgf8 mutant embryos displayed robust p38 activation both in the primitive streak and in cells that failed to migrate. The authors showed that, instead, p38IP–p38 is most likely activated downstream of Nck-interacting kinase (NIK; also a member of the MAPK cascade) as NIK mutant embryos failed to activate p38 and had similar meso- derm migration defects to p38IP mutants. However, this has yet to be shown directly. The findings by Zohn et al. therefore suggest that there are two path- ways acting in parallel to regulate E-cadherin levels and thus ensure a robust EMT during gastrulation. The FGF–Snail pathway regulates E-cadherin expression on a transcriptional level, whereas the p38IP– p38 pathway may act downstream of NIK to ensure efficient E-cad- herin protein downregulation. Although the role of NIK–p38IP–p38 has been examined here in the context of developmental EMT, loss of E-cadherin and EMT are also key events in tumour invasion and it would be interesting to see whether this Snail-independent pathway is also aberrantly controlled in tumour metastasis. MYRTO RAFTOPOULOU In E7.5 wild-type embryos (p38IP +/+ ), p38 (red) is activated throughout the embryo, whereas in mutant embryos (p38IP –/– ) p38 is not active in mesoderm that fails to migrate away from the primitive streak. Nature Publishing Group ©2006
Transcript of Embryonic EMTs intercepted by p38
654 NATURE CELL BIOLOGY VOLUME 8 | NUMBER 7 | JULY 2006
N E W S A N D V I E W S
In summary, this new study provides evi-dence for the specific presence of five RNAs in a centrosome fraction that has been cen-trifuged through the RNA-rich cytoplasm of the surf clam oocyte. This work should be applauded given the numerous techni-cal obstacles it faced. However, the incom-plete molecular characterization of the RNAs makes interpretation of the results difficult. Viewed in an epistemological and paradigmatic perspective, the progress made since the initial efforts12–15 now seems like a series of tentative steps. The findings of Alliegro et al. may be a triplet of steps forward.
ACKNOWLEDGEMENTSJoseph Gall (Carnegie Institution, Baltimore, MD) is gratefully acknowledged for kindly providing Fig. 1. The author wishes to pay tribute to his postdoctoral mentor, the late Elliott Robbins, an early investigator of centriole replication.
1. Wheatley, D. N. The Centriole: A Central Enigma of Cell Biology (Elsevier, Amsterdam and New York, 1982).
2. Wilson, E. B. The Cell in Development and Heredity 3rd edn (Macmillan, New York, 1925).
3. Gall, J. G. in Centrosomes in Development and Disease (ed. Nigg, E. A.) 3–15 (Wiley-VCH, Weinheim, 2004).
4. Sluder, G. & Hinchcliffe, E. H. Biol. Cell 91, 413–427 (1999).
5. Marshall, W. F. & Rosenbaum, J. L. Curr. Topics Dev. Biol. 49, 187–205 (2000).
6. Alliegro, M. C., Alliegro, M. A. & Palazzo, R. E. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0602859103 (2006).
7. Klotz, C. et al. J. Cell Biol. 110, 405–415 (1990).8. Reider, C. L. J. Cell Biol. 80, 1–9 (1979).9. Went, H. A. J. Theoret. Biol. 68, 95–100 (1977).10. Mello, C. C. & Conte, D., Jr Nature 431, 338–
342 (2004).11. Han, J. W., Park, J. H., Kim, M. & Lee, J. J. Cell Biol.
137, 871–879 (1997). 12. Seaman, G. R. Exp. Cell Res. 21, 292–302 (1960).13. Argetsinger, J. J. Cell Biol. 24, 154–157 (1965).14. Hoffman, E. J. J. Cell Biol. 25, 217–228 (1965).15. Dippel, R. V. J. Cell. Biol. 69, 622–637 (1976).16. Gall, J.G. A Pictorial History. Views of the Cell (American
Society for Cell Biology, Bethesda, 1996).17. Vogel, J.M., Stearns, T., Reider, C.L. & Palazzo, R.E. J.
Cell Biol. 137, 193–202 (1997).
Embryonic EMTs intercepted by p38
During development of the early embryo, gastrulation results in the formation of the three germ layers. For this process to occur, mesoderm cells need to undergo a rapid epithelial to mesenchymal transition (EMT) and migrate away from the primitive streak. A key step in EMTs is the suppression of E-cadherin through FGF signalling and increased expression of the transcription factor Snail. Zohn et al. now introduce a new, independent signalling pathway that regulates EMT, which involves members of the MAPK cascade (Cell, 125, 957–969; 2006).
The authors used an unbiased genetic screen to identify muta-tions that affect neural tube closure and gastrulation and stumbled on the mutant mouse line droopy eye (drey). drey encodes a p38-interacting protein (p38IP) and p38IP loss-of-function mutations cause severe development defects, including impaired migration of mesoderm cells from the primitive streak. The authors show that p38IP interacts with p38α in vitro and that this interaction is functionally relevant in vivo — embryonic tissues expressing p38IP truncation mutants that cannot bind p38 display impaired activation of p38 and its targets (see figure).
To elucidate the function of p38IP, the authors first looked at the known EMT candidates. In mutant mesoderm cells that failed to migrate away from the primitive streak, although Snail was expressed and E-cadherin mRNA was downregulated as in wild-type cells, E-cadherin protein remained localized to adherens junctions. Thus, it seems that p38IP-mutant mesoderm can initiate EMTs, but cannot effi-ciently complete the task. The p38IP-mutant mesoderm cells that failed to migrate in the embryo also failed to migrate when explanted and migration was rescued by blocking E-cadherin function. Furthermore, p38 activity was also required for E-cadherin downregulation and EMT, but not for cell migration per se.
Is the p38IP–p38 pathway also under the control of FGF signal-ling? Fgf8 mutant embryos displayed robust p38 activation both in the primitive streak and in cells that failed to migrate. The authors showed that, instead, p38IP–p38 is most likely activated downstream of Nck-interacting kinase (NIK; also a member of the MAPK cascade) as NIK mutant embryos failed to activate p38 and had similar meso-derm migration defects to p38IP mutants. However, this has yet to be shown directly.
The findings by Zohn et al. therefore suggest that there are two path-ways acting in parallel to regulate E-cadherin levels and thus ensure a robust EMT during gastrulation. The FGF–Snail pathway regulates E-cadherin expression on a transcriptional level, whereas the p38IP–p38 pathway may act downstream of NIK to ensure efficient E-cad-herin protein downregulation. Although the role of NIK–p38IP–p38 has been examined here in the context of developmental EMT, loss of E-cadherin and EMT are also key events in tumour invasion and it would be interesting to see whether this Snail-independent pathway is also aberrantly controlled in tumour metastasis.
MYRTO RAFTOPOULOU
In E7.5 wild-type embryos (p38IP+/+), p38 (red) is activated throughout the embryo, whereas in mutant embryos (p38IP–/–) p38 is not active in mesoderm that fails to migrate away from the primitive streak.
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