DEVELOPMENTAL BIOLOGY
The fetal liver is a niche for maturation of primitive erythroid cells
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Departments of *Medicine and
Developmental and Regenerative Biology, Oncological Sciences, and Gene and Cell Medicine, and
Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029
Communicated by Elaine Fuchs, The Rockefeller University, New York, NY, February 29, 2008 (received for review December 22, 2007)
Abstract
Primitive erythroid cells (EryP) are the earliest differentiated cell type of the mammalian embryo. They appear in the yolk sac by embryonic day 7.5, begin to enter the embryonic circulation 2 days later and continue to mature in a stepwise and synchronous fashion. Like their adult counterparts, EryP enucleate. However, EryP circulate throughout the embryo for several days before the first enucleated forms can be identified in the blood. We have used transgenic mouse lines in which GFP marks EryP to investigate this seemingly long lag and have identified a previously unrecognized developmental niche for EryP maturation. After exiting the yolk sac, EryP begin to express cell adhesion proteins, including 
4, 5, and β1 integrins, on their surface and migrate into the fetal liver (FL), where they interact with macrophages within erythroblastic islands. Binding of EryP to FL macrophages in vitro is stage-specific and partly depends on VCAM-1. The ability to tag and track EryP nuclei using a transgenic mouse line expressing an H2B-EGFP fusion allowed us to identify and characterize extruded EryP nuclei and to demonstrate that molecules such as 4, 5, and β1 integrins are redistributed onto the plasma membrane surrounding the extruding nucleus. FL macrophages engulf extruded EryP nuclei in cocultures and in the native FL in vivo. We conclude that EryP home to, complete their maturation, and enucleate within the FL, a tissue that is just developing as EryP begin to circulate. Our observations suggest a simple solution for a puzzling aspect of the development of the primitive erythroid lineage.
enucleation | mouse embryo | primitive erythropoiesis | fetal liver | macrophage
Author contributions: J.I. and S.T.F. contributed equally to this work; J.I., S.T.F., Z.H., and M.H.B. designed research; J.I., S.T.F., and Z.H. performed research; J.I., S.T.F., Z.H., and M.H.B. analyzed data; and M.H.B. wrote the paper.
The authors declare no conflict of interest.
To whom correspondence should be addressed. E-mail: margaret.baron{at}mssm.edu
© 2008 by The National Academy of Sciences of the USA
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