Journal
BLOOD
Volume 111, Issue 7, Pages 3313-3321Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-08-110114
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL069974, R01HL063169] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK062757] Funding Source: NIH RePORTER
- NHLBI NIH HHS [1P01HL69974, P01 HL069974, 1R01HL63169, R01 HL063169] Funding Source: Medline
- NIDDK NIH HHS [1R01DK062757, R01 DK062757] Funding Source: Medline
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Definitive hematopoietic stem and progenitor cells (HSCs/Ps) originating from the yolk sac and/or para-aorta-splanchno-pleura/aorta-gonad-mesone- phros 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 transplantation. 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 HSCs/Ps during very early embryonic development. Without Rac1, there was a decrease in circulating HSCs/Ps in the blood of embryonic day (E) 10.5 embryos, while yolk sac definitive hematopoiesis was quantitatively normal. Intraembryonic hematopoiesis was significantly impaired in Rac1-deficient embryos, culminating with absence of intra-aortic clusters and fetal liver hematopoiesis. At E10.5, Rac1-deficient HSCs/Ps displayed decreased 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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