Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1993 Dec 15;12(13):5065–5074. doi: 10.1002/j.1460-2075.1993.tb06200.x

Inhibition of hematopoietic development from embryonic stem cells by antisense vav RNA.

G M Wulf 1, C N Adra 1, B Lim 1
PMCID: PMC413767  PMID: 8262049

Abstract

The vav proto-oncogene is universally and specifically expressed in hematopoietic cells. vav contains a unique array of motifs allowing the protein to function as a signal transducer and possibly as a transcription factor. Under certain in vitro culture conditions murine embryonic stem cells develop into colonies containing multiple hematopoietic lineages. In embryonic stem cell lines, constitutively expressing high levels of antisense vav transcripts through a stably integrated transgene, differentiation into hematopoietic cells is disrupted. This observation presents the first evidence that vav has a critical role in the development of hematopoietic cells from totipotent cells.

Full text

PDF
5073

Images in this article

5066Image
on p.5066
5066Image
on p.5066
5066Image
on p.5066
5067Image
on p.5067
5067Image
on p.5067
5068Image
on p.5068
5068Image
on p.5068
5069Image
on p.5069
5069Image
on p.5069
5070Image
on p.5070
5070Image
on p.5070

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams J. M., Houston H., Allen J., Lints T., Harvey R. The hematopoietically expressed vav proto-oncogene shares homology with the dbl GDP-GTP exchange factor, the bcr gene and a yeast gene (CDC24) involved in cytoskeletal organization. Oncogene. 1992 Apr;7(4):611–618. [PubMed] [Google Scholar]
  2. Adra C. N., Boer P. H., McBurney M. W. Cloning and expression of the mouse pgk-1 gene and the nucleotide sequence of its promoter. Gene. 1987;60(1):65–74. doi: 10.1016/0378-1119(87)90214-9. [DOI] [PubMed] [Google Scholar]
  3. Arceci R. J., King A. A., Simon M. C., Orkin S. H., Wilson D. B. Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart. Mol Cell Biol. 1993 Apr;13(4):2235–2246. doi: 10.1128/mcb.13.4.2235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown J., Greaves M. F., Molgaard H. V. The gene encoding the stem cell antigen, CD34, is conserved in mouse and expressed in haemopoietic progenitor cell lines, brain, and embryonic fibroblasts. Int Immunol. 1991 Feb;3(2):175–184. doi: 10.1093/intimm/3.2.175. [DOI] [PubMed] [Google Scholar]
  5. Bustelo X. R., Ledbetter J. A., Barbacid M. Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates. Nature. 1992 Mar 5;356(6364):68–71. doi: 10.1038/356068a0. [DOI] [PubMed] [Google Scholar]
  6. Coppola J., Bryant S., Koda T., Conway D., Barbacid M. Mechanism of activation of the vav protooncogene. Cell Growth Differ. 1991 Feb;2(2):95–105. [PubMed] [Google Scholar]
  7. Egan S. E., Giddings B. W., Brooks M. W., Buday L., Sizeland A. M., Weinberg R. A. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993 May 6;363(6424):45–51. doi: 10.1038/363045a0. [DOI] [PubMed] [Google Scholar]
  8. Gale N. W., Kaplan S., Lowenstein E. J., Schlessinger J., Bar-Sagi D. Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature. 1993 May 6;363(6424):88–92. doi: 10.1038/363088a0. [DOI] [PubMed] [Google Scholar]
  9. Gulbins E., Coggeshall K. M., Baier G., Katzav S., Burn P., Altman A. Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation. Science. 1993 May 7;260(5109):822–825. doi: 10.1126/science.8484124. [DOI] [PubMed] [Google Scholar]
  10. Hill A., Hardies S. C., Phillips S. J., Davis M. G., Hutchison C. A., 3rd, Edgell M. H. Two mouse early embryonic beta-globin gene sequences. Evolution of the nonadult beta-globins. J Biol Chem. 1984 Mar 25;259(6):3739–3747. [PubMed] [Google Scholar]
  11. Katzav S., Martin-Zanca D., Barbacid M. vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells. EMBO J. 1989 Aug;8(8):2283–2290. doi: 10.1002/j.1460-2075.1989.tb08354.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Katzav S. vav: a molecule for all haemopoiesis? Br J Haematol. 1992 Jun;81(2):141–144. doi: 10.1111/j.1365-2141.1992.tb08198.x. [DOI] [PubMed] [Google Scholar]
  13. Keller G., Kennedy M., Papayannopoulou T., Wiles M. V. Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol Cell Biol. 1993 Jan;13(1):473–486. doi: 10.1128/mcb.13.1.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  15. Lelias J. M., Adra C. N., Wulf G. M., Guillemot J. C., Khagad M., Caput D., Lim B. cDNA cloning of a human mRNA preferentially expressed in hematopoietic cells and with homology to a GDP-dissociation inhibitor for the rho GTP-binding proteins. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1479–1483. doi: 10.1073/pnas.90.4.1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Li N., Batzer A., Daly R., Yajnik V., Skolnik E., Chardin P., Bar-Sagi D., Margolis B., Schlessinger J. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993 May 6;363(6424):85–88. doi: 10.1038/363085a0. [DOI] [PubMed] [Google Scholar]
  17. Lim B., Apperley J. F., Orkin S. H., Williams D. A. Long-term expression of human adenosine deaminase in mice transplanted with retrovirus-infected hematopoietic stem cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8892–8896. doi: 10.1073/pnas.86.22.8892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lindenbaum M. H., Grosveld F. An in vitro globin gene switching model based on differentiated embryonic stem cells. Genes Dev. 1990 Dec;4(12A):2075–2085. doi: 10.1101/gad.4.12a.2075. [DOI] [PubMed] [Google Scholar]
  19. Margolis B., Hu P., Katzav S., Li W., Oliver J. M., Ullrich A., Weiss A., Schlessinger J. Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. Nature. 1992 Mar 5;356(6364):71–74. doi: 10.1038/356071a0. [DOI] [PubMed] [Google Scholar]
  20. Matthews W., Jordan C. T., Wiegand G. W., Pardoll D., Lemischka I. R. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991 Jun 28;65(7):1143–1152. doi: 10.1016/0092-8674(91)90010-v. [DOI] [PubMed] [Google Scholar]
  21. McClanahan T., Dalrymple S., Barkett M., Lee F. Hematopoietic growth factor receptor genes as markers of lineage commitment during in vitro development of hematopoietic cells. Blood. 1993 Jun 1;81(11):2903–2915. [PubMed] [Google Scholar]
  22. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  23. Nocka K., Majumder S., Chabot B., Ray P., Cervone M., Bernstein A., Besmer P. Expression of c-kit gene products in known cellular targets of W mutations in normal and W mutant mice--evidence for an impaired c-kit kinase in mutant mice. Genes Dev. 1989 Jun;3(6):816–826. doi: 10.1101/gad.3.6.816. [DOI] [PubMed] [Google Scholar]
  24. Pahl H. L., Scheibe R. J., Zhang D. E., Chen H. M., Galson D. L., Maki R. A., Tenen D. G. The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter. J Biol Chem. 1993 Mar 5;268(7):5014–5020. [PubMed] [Google Scholar]
  25. Pevny L., Simon M. C., Robertson E., Klein W. H., Tsai S. F., D'Agati V., Orkin S. H., Costantini F. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature. 1991 Jan 17;349(6306):257–260. doi: 10.1038/349257a0. [DOI] [PubMed] [Google Scholar]
  26. Puil L., Pawson T. Vagaries of vav. Curr Biol. 1992 May;2(5):275–277. doi: 10.1016/0960-9822(92)90396-r. [DOI] [PubMed] [Google Scholar]
  27. Ridley A. J., Paterson H. F., Johnston C. L., Diekmann D., Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992 Aug 7;70(3):401–410. doi: 10.1016/0092-8674(92)90164-8. [DOI] [PubMed] [Google Scholar]
  28. Rozakis-Adcock M., Fernley R., Wade J., Pawson T., Bowtell D. The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature. 1993 May 6;363(6424):83–85. doi: 10.1038/363083a0. [DOI] [PubMed] [Google Scholar]
  29. Schmitt R. M., Bruyns E., Snodgrass H. R. Hematopoietic development of embryonic stem cells in vitro: cytokine and receptor gene expression. Genes Dev. 1991 May;5(5):728–740. doi: 10.1101/gad.5.5.728. [DOI] [PubMed] [Google Scholar]
  30. Simon M. C., Pevny L., Wiles M. V., Keller G., Costantini F., Orkin S. H. Rescue of erythroid development in gene targeted GATA-1- mouse embryonic stem cells. Nat Genet. 1992 May;1(2):92–98. doi: 10.1038/ng0592-92. [DOI] [PubMed] [Google Scholar]
  31. Spooncer E., Heyworth C. M., Dunn A., Dexter T. M. Self-renewal and differentiation of interleukin-3-dependent multipotent stem cells are modulated by stromal cells and serum factors. Differentiation. 1986;31(2):111–118. doi: 10.1111/j.1432-0436.1986.tb00391.x. [DOI] [PubMed] [Google Scholar]
  32. Spooncer E., Heyworth C. M., Dunn A., Dexter T. M. Self-renewal and differentiation of interleukin-3-dependent multipotent stem cells are modulated by stromal cells and serum factors. Differentiation. 1986;31(2):111–118. doi: 10.1111/j.1432-0436.1986.tb00391.x. [DOI] [PubMed] [Google Scholar]
  33. Whitelaw E., Tsai S. F., Hogben P., Orkin S. H. Regulated expression of globin chains and the erythroid transcription factor GATA-1 during erythropoiesis in the developing mouse. Mol Cell Biol. 1990 Dec;10(12):6596–6606. doi: 10.1128/mcb.10.12.6596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wiles M. V., Keller G. Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture. Development. 1991 Feb;111(2):259–267. doi: 10.1242/dev.111.2.259. [DOI] [PubMed] [Google Scholar]
  35. Zeger D. L., Osman N., Hennings M., McKenzie I. F., Sears D. W., Hogarth P. M. Mouse macrophage beta subunit (CD11b) cDNA for the CR3 complement receptor/Mac-1 antigen. Immunogenetics. 1990;31(3):191–197. doi: 10.1007/BF00211555. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES