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¹ Department of Developmental Biology and Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan
² Department of Medical Genetics, Research Institute for Microbial Diseases, Osaka University
³ Department of Developmental Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
⁴ The Terry Fox Laboratory, British Columbia Cancer Agency and the Department of Medicine, University of British Columbia, Vancouver, BC, Canada V5Z 1L3

Address correspondence to Yoshihiro Takihara, Dept. of Developmental Biology and Medicine, Osaka Medical Center for Cancer and Cardiovascular Diseases, 3-3, Nakamichi-1, Higashinari, Osaka 537-8511, Japan. Phone: 81-6-6972-1181 (4116); Fax: 81-6-6973-5691; E-mail: takihara-yo{at}mc.pref.osaka.jp

The rae28 gene (rae28), also designated as mph1, is a mammalian ortholog of the Drosophila polyhomeotic gene, a member of Polycomb group genes (PcG). rae28 constitutes PcG complex 1 for maintaining transcriptional states which have been once initiated, presumably through modulation of the chromatin structure. Hematopoietic activity was impaired in the fetal liver of rae28-deficient animals (rae28^-/-), as demonstrated by progressive reduction of hematopoietic progenitors of multilineages and poor expansion of colony forming units in spleen (CFU-S₁₂) during embryonic development. An in vitro long-term culture-initiating cell assay suggested a reduction in hematopoietic stem cells (HSCs), which was confirmed in vivo by reconstitution experiments in lethally irradiated congenic recipient mice. The competitive repopulating units (CRUs) reflect HSCs supporting multilineage blood-cell production. CRUs were generated, whereas the number of CRUs was reduced by a factor of 20 in the rae28^-/- fetal liver. We also performed serial transplantation experiments to semiquantitatively measure self-renewal activity of CRUs in vivo. Self-renewal activity of CRUs was 15-fold decreased in rae28^-/-. Thus the compromised HSCs were presumed to reduce hematopoietic activity in the rae28^-/- fetal liver. This is the first report to suggest that rae28 has a crucial role in sustaining the activity of HSCs to maintain hematopoiesis.

Key Words: Polycomb group genes • rae28 • hematopoiesis • hematopoietic stem cells • self-renewal

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