The Journal of Experimental Medicine
StemCell Technologies
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Published online 9 February 2004 doi:10.1084/jem.20031800
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 491-502
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B Lineage–specific Regulation of V(D)J Recombinase Activity Is Established in Common Lymphoid Progenitors

Lisa Borghesi1, Lih-Yun Hsu2, Juli P. Miller3, Michael Anderson{dagger}, Leonard Herzenberg4, Leonore Herzenberg4, Mark S. Schlissel2, David Allman3, and Rachel M. Gerstein1

1 Molecular Genetics and Microbiology, University of Massachusetts Medical School (UMMS), Worcester, MA 01655
2 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720
3 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
4 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305

Address correspondence to Rachel M. Gerstein, Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave. North, S5-714, Worcester, MA 01655. Phone: (508) 856-1044; Fax: (508) 856 5920; email: rachel.gerstein{at}umassmed.edu

Expression of V(D)J recombinase activity in developing lymphocytes is absolutely required for initiation of V(D)J recombination at antigen receptor loci. However, little is known about when during hematopoietic development the V(D)J recombinase is first active, nor is it known what elements activate the recombinase in multipotent hematopoietic progenitors. Using mice that express a fluorescent transgenic V(D)J recombination reporter, we show that the V(D)J recombinase is active as early as common lymphoid progenitors (CLPs) but not in the upstream progenitors that retain myeloid lineage potential. Evidence of this recombinase activity is detectable in all four progeny lineages (B, T, and NK, and DC), and rag2 levels are the highest in progenitor subsets immediately downstream of the CLP. By single cell PCR, we demonstrate that V(D)J rearrangements are detectable at IgH loci in ~5% of splenic natural killer cells. Finally, we show that recombinase activity in CLPs is largely controlled by the Erag enhancer. As activity of the Erag enhancer is restricted to the B cell lineage, this provides the first molecular evidence for establishment of a lineage-specific transcription program in multipotent progenitors.

Key Words: B lymphopoiesis • V(D)J recombination • lineage restriction • hematopoiesis • stem cell • transcription

The online version of this article contains supplemental material.

Abbreviations used in this paper: CJ, coding joint; CLP, common lymphoid progenitor; ETP, early thymic T lineage progenitor; RAG, recombinase-activating gene; RSS, recombination signal sequence; SJ, signal joint.

{dagger} Dr. Michael Anderson died on September 20, 2002.


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