Rac1 is essential for intraembryonic hematopoiesis and for the initial seeding of fetal liver with definitive hematopoietic progenitor cells.
Definitive hematopoietic stem and progenitor cells (HSCs/Ps) originating from the yolk sac and/or para-aorta-splanchno-pleura/aorta-gonad-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 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 inter-action 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.
Ghiaur
Gabriel
G
Department of Pediatrics, Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, and Hoxworth Blood Center, University of Cincinnati College of Medicine, OH, USA.
Ferkowicz
Michael J
MJ
Milsom
Michael D
MD
Bailey
Jeff
J
Witte
David
D
Cancelas
Jose A
JA
Yoder
Mervin C
MC
Williams
David A
DA
D000818:Animals; D001853:Bone Marrow / Q000196:embryology; D002465:Cell Movement / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology; D005260:Female; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000196:embryology; D008297:Male; D008650:Mesonephros / Q000166:cytology / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D015017:Yolk Sac / Q000166:cytology / Q000196:embryology; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein