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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3313-3321.
Prepublished online as a Blood First Edition Paper on December 14, 2007; DOI 10.1182/blood-2007-08-110114.
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Submitted August 31, 2007
Accepted November 9, 2007
Rac1 is essential for intraembryonic hematopoiesis and for the initial seeding of fetal liver with definitive hematopoietic progenitor cells
Gabriel Ghiaur, Michael J Ferkowicz, Michael D Milsom, Jeff Bailey, David Witte, Jose A Cancelas, Mervin C Yoder, and David A Williams*
Division of Experimental Hematology, Department of Pediatrics, Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
Division of Pathology, Department of Pediatrics, Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States
* Corresponding author; email: dawilliams{at}childrens.harvard.edu.
Definitive hematopoietic stem and progenitor cells (HSC/P) originating from the yolk sac and/or para-aorta-splanchno-pleura/aorta-gonado-mesonephros are hypothesized to colonize the fetal liver, but mechanisms involved are poorly defined. The Rac subfamily of Rho GTPases has been shown to play essential roles in HSC/P localization to the bone marrow following transplantation1. Here, we study the role of Rac1 in HSC/P migration during ontogeny and seeding of fetal liver. Using a triple transgenic approach, we have deleted Rac1 in HSC/P during very early embryonic development. In the absence of Rac1, there is decrease in circulating HSC/P in the blood of E10.5 embryos while yolk sac definitive hematopoiesis was quantitatively normal. Intraembryonic hematopoiesis was significantly impaired in Rac1 deficient embryos, culminating with absence of intraaortic clusters and fetal liver hematopoiesis. At E10.5, Rac1 deficient HSC/P displayed decrease transwell migration and impaired interaction with the microenvironment in migration-dependent assays. These data suggest that Rac1 plays an important role in HSC/P migration during embryonic development and is essential for the emergence of intraembryonic hematopoiesis.
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