Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization

doi:10.1073/pnas.101546898

Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization

^*Howard Hughes Medical Institute, ^†Section of Pediatric Hematology/Oncology, Herman B Wells Center for Pediatric Research, Department of Pediatrics, and ^§Section of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; and ^‖Department of Biochemistry, University of Tennessee, Memphis, TN 38163

Edited by Richard O. Hynes, Massachusetts Institute of Technology, Cambridge, MA, and approved March 9, 2001 (received for review November 17, 2000)

Abstract

Critical to homeostasis of blood cell production by hematopoietic stem/progenitor (HSC/P) cells is the regulation of HSC/P retention within the bone marrow microenvironment and migration between the bone marrow and the blood. Key extracellular regulatory elements for this process have been defined (cell–cell adhesion, growth factors, chemokines), but the mechanism by which HSC/P cells reconcile multiple external signals has not been elucidated. Rac and related small GTPases are candidates for this role and were studied in HSC/P deficient in Rac2, a hematopoietic cell-specific family member. Rac2 appears to be critical for HSC/P adhesion both in vitro and in vivo, whereas a compensatory increase in Cdc42 activation regulates HSC/P migration. This genetic analysis provides physiological evidence of cross-talk between GTPase proteins and suggests that a balance of these two GTPases controls HSC/P adhesion and mobilization in vivo.

Footnotes

↵ ‡ F.-C.Y. and S.J.A. contributed equally to this work.
↵ ¶ Present address: Walter and Eliza Hall Institute, Melbourne, Australia 3050.
↵ ** To whom reprint requests should be addressed at: Howard Hughes Medical Institute, Indiana University School of Medicine, 1044 West Walnut Street, Room 402, Indianapolis, IN 46202. E-mail: dwilliam{at}iupui.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

HSC/P cells,

hematopoietic stem/progenitor cells;

HM,

hematopoietic microenvironment;

G-CSF,

granulocyte colony-stimulating factor;

CFU-S12,

day 12 colony-forming units-spleen;

CFU-C,

in vitro colony-forming units;

FN,

fibronectin;

WT,

wild type;

ADF,

actin-depolymerizing factor;

SDF-1,

stromal-derived factor-1;

PAK1,

p21-activated kinase-1;

GST,

glutathione-S-transferase