Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Snail1 controls TGF-β responsiveness and differentiation of mesenchymal stem cells

Oncogene volume 32, pages 3381–3389 (2013)Cite this article

Subjects

Abstract

The Snail1 transcriptional repressor plays a key role in triggering epithelial-to-mesenchymal transition. Although Snail1 is widely expressed in early development, in adult animals it is limited to a subset of mesenchymal cells where it has a largely unknown function. Using a mouse model with inducible depletion of Snail1, here we demonstrate that Snail1 is required to maintain mesenchymal stem cells (MSCs). This effect is associated to the responsiveness to transforming growth factor (TGF)-β1 that shows a strong Snail1 dependence. Snail1 depletion in conditional knockout adult animals causes a significant decrease in the number of bone marrow-derived MSCs. In culture, Snail1-deficient MSCs prematurely differentiate to osteoblasts or adipocytes and, in contrast to controls, are resistant to the TGF-β1-induced differentiation block. These results demonstrate a new role for Snail1 in TGF-β response and MSC maintenance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Peinado H, Olmeda D, Snail Cano A. . ZEB and bHLH factors in tumour progression: and alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415–428.

    Article  CAS  Google Scholar 

  2. Garcia de Herreros A, Peiro S, Nassour M, Savagner P . Snail family regulation and epithelial-mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia 2010; 15: 135–147.

    Article  Google Scholar 

  3. Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000; 2: 84–89.

    Article  CAS  Google Scholar 

  4. Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000; 2: 76–83.

    Article  CAS  Google Scholar 

  5. Solanas G, Porta-de-la-Riva M, Agustí C, Casagolda D, Sánchez-Aguilera F, Larriba MJ et al. E-cadherin controls beta-catenin and NF-kappaB transcriptional activity in mesenchymal gene expression. J Cell Sci 2008; 121: 2224–2234.

    Article  CAS  Google Scholar 

  6. Stanisavljevic J, Porta-de-la-Riva M, Batlle R, García de Herreros A, Baulida J . The p65 subunit of NF-kB and PARP1 assist Snail1 in activating Fibronectin transcription. J. Cell Sci 2011; 124: 4161–4171.

    Article  CAS  Google Scholar 

  7. Carver EA, Jiang R, Lan Y, Oram KF, Gridley T . The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol 2001; 21: 8184–8188.

    Article  CAS  Google Scholar 

  8. Murray SA, Gridley T . Snail family genes are required for left-right asymmetry determination, but not neural crest formation, in mice. Proc Natl Acad Sci USA 2006; 103: 10300–10304.

    Article  CAS  Google Scholar 

  9. Francí C, Takkunen M, Dave N, Alameda F, Gómez S, Rodríguez R et al. Expression of Snail protein in tumor-stroma interface. Oncogene 2006; 25: 5134–5144.

    Article  Google Scholar 

  10. Francí C, Gallén M, Alameda F, Baró T, Iglesias M, Virtanen I et al. Snail1 protein in the stroma as a new putative prognosis marker for colon tumours. PLoS One 2009; 4: e5595.

    Article  Google Scholar 

  11. Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nat Cell Biol 2009; 11: 943–950.

    Article  CAS  Google Scholar 

  12. Rowe RG, Li XY, Hu Y, Saunders TL, Virtanen I, Garcia de Herreros A et al. Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs. J Cell Biol 2009; 184: 399–408.

    Article  CAS  Google Scholar 

  13. Peinado H, Quintanilla M, Cano A . Transforming growth factor TGF-b1 induces Snail transcription factor in epithelial cell lines. J Biol Chem 2003; 278: 21113–21123.

    Article  CAS  Google Scholar 

  14. Ignotz RA, Massague J . Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc Natl Acad Sci USA 1985; 82: 8530–8534.

    Article  CAS  Google Scholar 

  15. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  16. DaCosta Byfeled S, Major C, Laping NJ, Roberts AB . SB-505124 is a selective inhibitor of transforming growth factor-beta I type I receptors ALK4, ALK5 and ALK7. Mol Pharmacol 2004; 65: 744–752.

    Article  Google Scholar 

  17. Sawyer JS, Anderson BD, Beight DW, Campbell RM, Jones ML, Herron DK et al. Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. J Med Chem 2003; 46: 3953–3956.

    Article  CAS  Google Scholar 

  18. Ryu JM, Lee MY, Yun SP, Han HJ . High glucose regulates cyclin D1/E of human mesenhcymal stem cells through TGF-β1 expression via Ca2+/PKC/MAPKs and PI3K/Akt/mTOR signal pathways. J Cell Physiol 2010; 224: 59–70.

    CAS  PubMed  Google Scholar 

  19. Escrivà M, Peiró S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentís B et al. Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol 2008; 28: 1528–1540.

    Article  Google Scholar 

  20. Dezawa M, Ishikawa H, Itokazu Y, Yoshihara T, Hoshino M, Takeda S et al. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 2005; 309: 314–317.

    Article  CAS  Google Scholar 

  21. de Frutos CA, Vega S, Manzanares M, Flores JM, Huertas H, Martínez-Frías ML et al. Snail1 is a transcriptional effector of FGF3 signaling during chondrogenesis and achondroplasias. Dev Cell 2007; 13: 872–883.

    Article  CAS  Google Scholar 

  22. de Frutos CA, Dacquin R, Vega S, Jurdic P, Machuca-Gayet I, Nieto MA . Snail1 controls bone mass by regulating Runx2 and VDR expression during osteoblast differentiation. EMBO J 2009; 28: 686–696.

    Article  CAS  Google Scholar 

  23. Pérez-Mancera PA, Bermejo-Rodríguez C, González-Herrero I, Herranz M, Flores T, Jiménez R et al. Adipose tissue mass is modulated by SLUG (SNAI2). Hum Mol Genet 2007; 16: 2972–2986.

    Article  Google Scholar 

  24. Peiró S, Escrivà M, Puig I, Barberà MJ, Dave N, Herranz N et al. Snail1 transcriptional repressor binds its own promoter and controls its expression. Nucl Acids Res 2006; 34: 2077–2084.

    Article  Google Scholar 

  25. Runyan CE, Schnaper HW, Poncelet AC . The phosphatidylinositol 3-kinase/Akt pathway enhances Smad3-stimulated mesangial cell collagen I expression in response to transforming growth factor-b1. J Biol Chem 2004; 279: 2632–2639.

    Article  CAS  Google Scholar 

  26. Ghosh Choudhury G, Abboud HE . Tyrosine phosphorylation-dependent PI3 Kinase/Akt signal transduction regulates TGF-β-induced fibronectin expression in mesangial cells. Cell Signal 2004; 16: 31–41.

    Article  Google Scholar 

  27. Yi JY, Shin I, Arteaga CL . Type I transforming growth factor b receptor binds to and activates phosphatidylinositol 3-kinase. J Biol Chem 2005; 280: 10870–10876.

    Article  CAS  Google Scholar 

  28. Vega S, Morales AV, Ocaña OH, Valdés F, Fabregat I, Nieto MA . Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18: 1131–1143.

    Article  CAS  Google Scholar 

  29. Villagrasa P, Díaz VM, Viñas-Castells R, Peiró S, Del Valle-Pérez B, Dave N et al. Akt2 interacts with Snail1 in the E-cadherin promoter. Oncogene 2011; 31: 4064–4075.

    Google Scholar 

  30. Hill R, Wu H . PTEN, stem cells and cancer stem cells. J Biol Chem 2009; 284: 11755–11759.

    Article  CAS  Google Scholar 

  31. Wu X, Chen S, Orlando SA, Yuan J, Kim ET, Munugalavadla V et al. p85α regulates osteoblast differentiation by cross-talking with the MAPK pathway. J Biol Chem 2011; 286: 13512–13521.

    Article  CAS  Google Scholar 

  32. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 2005; 171: 1023–1034.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Mukherjee A, Rotwein P . Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development. Mol Cell Biol 2012; 32: 490–500.

    Article  CAS  Google Scholar 

  34. Murray SA, Carver EA, Gridley T . Generation of a Snail1 (Snai1) conditional null allele. Genesis 2006; 44: 7–11.

    Article  CAS  Google Scholar 

  35. Soleimani M, Nadri S . A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc 2009; 4: 102–106.

    Article  CAS  Google Scholar 

  36. Bellacosa A, Chan TO, Ahmed NN, Datta K, Malstrom S, Stokoe D et al. Akt activation by growth factors is a multi-step process: the role of the PH domain. Oncogene 1998; 17: 313–325.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M Massoumi for help in the preparation of MSCs, Td’Altri for assistance in the FACS analysis, N García-Giralt and L Larue for reagents, L diCroce for comments and E Batlle for support and advice. This study was funded by a grant awarded by la Fundación Científica de la Asociación Española contra el Cáncer to AGH, JIC and FB. Support from the Ministerio de Ciencia y Tecnología (SAF2006-00339 and SAF2010-16089) and Fundació La Marató de TV3 to AGH, and NIH R01HD034883 to TG is also appreciated. We also acknowledge support from ISCIII/FEDER (RD06/0020/0109, RD06/0020/0040, RD06/0020/0020), Generalitat de Catalunya (2009SGR867). RB and LA-C were recipients from FPI predoctoral fellowships.

Author information

Authors and Affiliations

  1. Programa de Recerca en Càncer, IMIM-Hospital del Mar, Barcelona, Spain

    R Batlle, L Alba-Castellón, J Loubat-Casanovas, E Armenteros, C Francí, J Stanisavljevic, J Baulida & A García de Herreros

  2. Departamento de Medicina Molecular, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain

    R Banderas & J I Casal

  3. Animal Facility, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain

    J Martin-Caballero

  4. Servicio de Oncologia Médica, Hospital Puerta de Hierro, Majadahonda, Spain

    F Bonilla

  5. Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA

    T Gridley

  6. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    A García de Herreros

Authors
  1. R Batlle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Alba-Castellón
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Loubat-Casanovas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Armenteros
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Francí
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Stanisavljevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Banderas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Martin-Caballero
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Bonilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Baulida
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J I Casal
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. T Gridley
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A García de Herreros
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A García de Herreros.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Batlle, R., Alba-Castellón, L., Loubat-Casanovas, J. et al. Snail1 controls TGF-β responsiveness and differentiation of mesenchymal stem cells. Oncogene 32, 3381–3389 (2013). https://doi.org/10.1038/onc.2012.342

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.342

Keywords

This article is cited by

Search

Advanced search

Quick links