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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Dec 20;91(26):12755–12759. doi: 10.1073/pnas.91.26.12755

Hematopoietic development of vav-/- mouse embryonic stem cells.

R Zhang 1, F Y Tsai 1, S H Orkin 1
PMCID: PMC45518  PMID: 7809116

Abstract

The vav protooncogene product is expressed nearly exclusively in hematopoietic lineages and contains several structural motifs (SH2/SH3 domains and a dbl-oncogene homology region) typical of proteins functioning in signaling pathways. To ascertain if vav expression is required for hematopoiesis we generated vav-negative mouse embryonic stem cells by gene targeting and examined the consequences of loss of vav function on erythroid and myeloid development in vitro and in vivo. In conflict with the conclusions drawn from expression of antisense vav RNA in embryonic stem cells [Wulf, G. M., Adra, C. N. & Lim, B. (1993) EMBO J. 12, 5065-5074], we observed erythroid and myeloid development in the absence of vav. These experiments demonstrate that vav expression is not absolutely required for hematopoietic development.

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Selected References

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  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. Alai M., Mui A. L., Cutler R. L., Bustelo X. R., Barbacid M., Krystal G. Steel factor stimulates the tyrosine phosphorylation of the proto-oncogene product, p95vav, in human hemopoietic cells. J Biol Chem. 1992 Sep 5;267(25):18021–18025. [PubMed] [Google Scholar]
  3. Boguski M. S., Bairoch A., Attwood T. K., Michaels G. S. Proto-vav and gene expression. Nature. 1992 Jul 9;358(6382):113–113. doi: 10.1038/358113a0. [DOI] [PubMed] [Google Scholar]
  4. Burkert U., von Rüden T., Wagner E. F. Early fetal hematopoietic development from in vitro differentiated embryonic stem cells. New Biol. 1991 Jul;3(7):698–708. [PubMed] [Google Scholar]
  5. Bustelo X. R., Barbacid M. Tyrosine phosphorylation of the vav proto-oncogene product in activated B cells. Science. 1992 May 22;256(5060):1196–1199. doi: 10.1126/science.256.5060.1196. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Bustelo X. R., Suen K. L., Leftheris K., Meyers C. A., Barbacid M. Vav cooperates with Ras to transform rodent fibroblasts but is not a Ras GDP/GTP exchange factor. Oncogene. 1994 Aug;9(8):2405–2413. [PubMed] [Google Scholar]
  8. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Evans G. A., Howard O. M., Erwin R., Farrar W. L. Interleukin-2 induces tyrosine phosphorylation of the vav proto-oncogene product in human T cells: lack of requirement for the tyrosine kinase lck. Biochem J. 1993 Sep 1;294(Pt 2):339–342. doi: 10.1042/bj2940339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Harris N., Super M., Rits M., Chang G., Ezekowitz R. A. Characterization of the murine macrophage mannose receptor: demonstration that the downregulation of receptor expression mediated by interferon-gamma occurs at the level of transcription. Blood. 1992 Nov 1;80(9):2363–2373. [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. 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]
  16. Mansour S. L., Thomas K. R., Capecchi M. R. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988 Nov 24;336(6197):348–352. doi: 10.1038/336348a0. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Mortensen R. M., Conner D. A., Chao S., Geisterfer-Lowrance A. A., Seidman J. G. Production of homozygous mutant ES cells with a single targeting construct. Mol Cell Biol. 1992 May;12(5):2391–2395. doi: 10.1128/mcb.12.5.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Robertson E., Bradley A., Kuehn M., Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature. 1986 Oct 2;323(6087):445–448. doi: 10.1038/323445a0. [DOI] [PubMed] [Google Scholar]
  22. Royer-Pokora B., Kunkel L. M., Monaco A. P., Goff S. C., Newburger P. E., Baehner R. L., Cole F. S., Curnutte J. T., Orkin S. H. Cloning the gene for an inherited human disorder--chronic granulomatous disease--on the basis of its chromosomal location. Nature. 1986 Jul 3;322(6074):32–38. doi: 10.1038/322032a0. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Tybulewicz V. L., Crawford C. E., Jackson P. K., Bronson R. T., Mulligan R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991 Jun 28;65(7):1153–1163. doi: 10.1016/0092-8674(91)90011-m. [DOI] [PubMed] [Google Scholar]
  25. Weiss M. J., Keller G., Orkin S. H. Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells. Genes Dev. 1994 May 15;8(10):1184–1197. doi: 10.1101/gad.8.10.1184. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Wulf G. M., Adra C. N., Lim B. Inhibition of hematopoietic development from embryonic stem cells by antisense vav RNA. EMBO J. 1993 Dec 15;12(13):5065–5074. doi: 10.1002/j.1460-2075.1993.tb06200.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. te Riele H., Maandag E. R., Clarke A., Hooper M., Berns A. Consecutive inactivation of both alleles of the pim-1 proto-oncogene by homologous recombination in embryonic stem cells. Nature. 1990 Dec 13;348(6302):649–651. doi: 10.1038/348649a0. [DOI] [PubMed] [Google Scholar]

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