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Rho GTPase Cdc42 is essential for human T-cell development

Kaatje Smits, Veronica Iannucci UGent, Veronique Stove UGent, Peter Van Hauwe, Evelien Naessens UGent, Pieter Meuwissen UGent, Kevin Ariën UGent, Mostafa Bentahir UGent, Jean Plum UGent and Bruno Verhasselt UGent (2010) HAEMATOLOGICA-THE HEMATOLOGY JOURNAL. 95(3). p.367-375
abstract
Background: Rho GTPases are involved in the regulation of many cell functions, including some related to the actin cytoskeleton. Different Rho GTPases have been shown to be important for T-cell development in mice. However, their role in human T-cell development has not yet been explored. Design and Methods: We examined the expression and activation of Rho GTPases along different stages of T-cell development in the human thymus. Early stage human thymocytes were transduced with constitutively active and dominant negative mutants of different Rho GTPases to explore their role in human T-cell development, as analyzed in fetal thymus organ cultures. The use of these mutants as well as Rho GTPase-specific inhibitors allowed us to explore the role of GTPases in thymocyte migration. Results: We found that the expression of several Rho GTPases is differently regulated during successive stages of T-cell development in man, suggesting a specific role in human thymopoiesis. In chimeric fetal thymus organ culture, T-cell development was not or only mildly affected by expression of dominant negative Rac1 and Rac2, but was severely impaired in the presence of dominant negative Cdc42, associated with enhanced apoptosis and reduced proliferation. Kinetic analysis revealed that Cdc42 is necessary in human T-cell development both before and after expression of the pre-T-cell receptor. Using inhibitors and retrovirally transferred mutants of the aforementioned Rho GTPases, we showed that only Rac1 is necessary for migration of different thymocyte subsets, including the early CD34(+) fraction, towards stromal cell-derived factor-la. Constitutively active mutants of Rac1, Rac2 and Cdc42 all impaired migration towards stromal cell-derived factor-la and T-cell development to different degrees. Conclusions: This is the first report on Rho GTPases in human T-cell development, showing the essential role of Cdc42. Our data suggest that enhanced apoptotic death and reduced proliferation rather than disturbed migration explains the decreased thymopoiesis induced by dominant negative Cdc42.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
RAC, PROTEINS, IN-VIVO, CYCLIN D3, THYMUS, hematopoietic stem cells, T lymphocytes, lymphopoiesis, Rho GTP-binding proteins, EXPRESSION, ENGRAFTMENT, DIFFERENTIATION, PROLIFERATION, Rac GTP-binding proteins, HEMATOPOIETIC STEM
journal title
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
Haematol-Hematol. J.
volume
95
issue
3
pages
367 - 375
Web of Science type
Article
Web of Science id
000276292100007
JCR category
HEMATOLOGY
JCR impact factor
6.532 (2010)
JCR rank
7/65 (2010)
JCR quartile
1 (2010)
ISSN
0390-6078
DOI
10.3324/haematol.2009.006890
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1252566
handle
http://hdl.handle.net/1854/LU-1252566
date created
2011-06-06 10:32:36
date last changed
2011-06-16 09:45:34
@article{1252566,
  abstract     = {Background: Rho GTPases are involved in the regulation of many cell functions, including some related to the actin cytoskeleton. Different Rho GTPases have been shown to be important for T-cell development in mice. However, their role in human T-cell development has not yet been explored. Design and Methods: We examined the expression and activation of Rho GTPases along different stages of T-cell development in the human thymus. Early stage human thymocytes were transduced with constitutively active and dominant negative mutants of different Rho GTPases to explore their role in human T-cell development, as analyzed in fetal thymus organ cultures. The use of these mutants as well as Rho GTPase-specific inhibitors allowed us to explore the role of GTPases in thymocyte migration. Results: We found that the expression of several Rho GTPases is differently regulated during successive stages of T-cell development in man, suggesting a specific role in human thymopoiesis. In chimeric fetal thymus organ culture, T-cell development was not or only mildly affected by expression of dominant negative Rac1 and Rac2, but was severely impaired in the presence of dominant negative Cdc42, associated with enhanced apoptosis and reduced proliferation. Kinetic analysis revealed that Cdc42 is necessary in human T-cell development both before and after expression of the pre-T-cell receptor. Using inhibitors and retrovirally transferred mutants of the aforementioned Rho GTPases, we showed that only Rac1 is necessary for migration of different thymocyte subsets, including the early CD34(+) fraction, towards stromal cell-derived factor-la. Constitutively active mutants of Rac1, Rac2 and Cdc42 all impaired migration towards stromal cell-derived factor-la and T-cell development to different degrees. Conclusions: This is the first report on Rho GTPases in human T-cell development, showing the essential role of Cdc42. Our data suggest that enhanced apoptotic death and reduced proliferation rather than disturbed migration explains the decreased thymopoiesis induced by dominant negative Cdc42.},
  author       = {Smits, Kaatje and Iannucci, Veronica and Stove, Veronique and Van Hauwe, Peter and Naessens, Evelien and Meuwissen, Pieter and Ari{\"e}n, Kevin and Bentahir, Mostafa and Plum, Jean and Verhasselt, Bruno},
  issn         = {0390-6078},
  journal      = {HAEMATOLOGICA-THE HEMATOLOGY JOURNAL},
  keyword      = {RAC,PROTEINS,IN-VIVO,CYCLIN D3,THYMUS,hematopoietic stem cells,T lymphocytes,lymphopoiesis,Rho GTP-binding proteins,EXPRESSION,ENGRAFTMENT,DIFFERENTIATION,PROLIFERATION,Rac GTP-binding proteins,HEMATOPOIETIC STEM},
  language     = {eng},
  number       = {3},
  pages        = {367--375},
  title        = {Rho GTPase Cdc42 is essential for human T-cell development},
  url          = {http://dx.doi.org/10.3324/haematol.2009.006890},
  volume       = {95},
  year         = {2010},
}

Chicago
Smits, Kaatje, Veronica Iannucci, VERONIQUE STOVE, Peter Van Hauwe, Evelien Naessens, Pieter Meuwissen, Kevin Ariën, Mostafa Bentahir, Jean Plum, and Bruno Verhasselt. 2010. “Rho GTPase Cdc42 Is Essential for Human T-cell Development.” Haematologica-the Hematology Journal 95 (3): 367–375.
APA
Smits, Kaatje, Iannucci, V., STOVE, V., Van Hauwe, P., Naessens, E., Meuwissen, P., Ariën, K., et al. (2010). Rho GTPase Cdc42 is essential for human T-cell development. HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, 95(3), 367–375.
Vancouver
1.
Smits K, Iannucci V, STOVE V, Van Hauwe P, Naessens E, Meuwissen P, et al. Rho GTPase Cdc42 is essential for human T-cell development. HAEMATOLOGICA-THE HEMATOLOGY JOURNAL. 2010;95(3):367–75.
MLA
Smits, Kaatje, Veronica Iannucci, VERONIQUE STOVE, et al. “Rho GTPase Cdc42 Is Essential for Human T-cell Development.” HAEMATOLOGICA-THE HEMATOLOGY JOURNAL 95.3 (2010): 367–375. Print.