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Human Molecular Genetics, 2000, Vol. 9, No. 3 387-394
© 2000 Oxford University Press

Huntingtin is required for normal hematopoiesis

Martina Metzler1,+, Cheryl D. Helgason2,+, Ioannis Dragatsis3, Taiqi Zhang1, Lu Gan1, Nicolas Pineault2, Scott O. Zeitlin4, R. Keith Humphries2,5,+ and Michael R. Hayden1,+,§

1Center for Molecular Medicine and Therapeutics, University of British Columbia, Department of Medical Genetics, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4, 2The Terry Fox Laboratory, British Columbia Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3, 3Department of Genetics and Development, Columbia University, Russ Berrie Center, Room 607, 1150 St Nicholas Avenue, New York, NY 10032, USA, 4Department of Pathology, Columbia University and 5Department of Medicine, University of British Columbia

Huntington’s disease (HD) is a neurodegenerative disease associated with polyglutamine expansion in huntingtin, a widely expressed protein. The function of huntingtin is unknown although huntingtin plays a fundamental role in development since gene targeted HD –/– mouse embryos die shortly after gastrulation. Expression of huntingtin is detected in spleen and thymus but its role in hematopoiesis has not been examined. To determine the function of huntingtin and to provide insight into potential pathologic mechanisms in HD, we analyzed the role of huntingtin in hematopoietic development. Expression of huntingtin was analyzed in a variety of hematopoietic cell types, and in vitro hematopoiesis was assessed using an HD +/– and several HD –/– embryonic stem (ES) cell lines. Although wild-type, HD +/– and HD –/– ES cell lines formed primary embryoid bodies (EBs) with similar efficiency, the numbers of hematopoietic progenitors detected at various stages of the in vitro differentiation were reduced in HD +/– and HD –/– ES cell lines examined. Expression analyses of hematopoietic markers within the EBs revealed that primitive and definitive hematopoiesis occurs in the absence of huntingtin. However, further analysis using a suspension culture in the presence of hematopoietic cytokines demonstrated a highly significant gene dosage-dependent decrease in proliferation and/or survival of HD +/– and HD –/– cells. Enrichment for the CD34+ cells within the EB confirmed that the impairment is intrinsic to the hematopoietic cells. These obser- vations suggest that huntingtin expression is required for the generation and expansion of hematopoietic cells and provides an alternative system in which to assess the function of huntingtin.

+ These authors contributed equally to this work

§ To whom correspondence should be addressed. Tel: +1 604 875 3535; Fax: +1 604 875 3819; Email: mrh@cmmt.ubc.ca


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