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J. Biol. Chem., Vol. 280, Issue 50, 41636-41644, December 16, 2005

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Distinct Roles for SCL in Erythroid Specification and Maturation in Zebrafish^*

Marianne A. Juarez, Fengyun Su, Sang Chun, Mark J. Kiel, and Susan E. Lyons1

From the Department of Internal Medicine, Division of Hematology-Oncology and Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan 48109 and the Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan 48109

The stem cell leukemia (SCL) transcription factor is essential for vertebrate hematopoiesis. Using the powerful zebrafish model for embryonic analysis, we compared the effects of either reducing or ablating Scl using morpholino-modified antisense RNAs. Ablation of Scl resulted in the loss of primitive and definitive hematopoiesis, consistent with its essential role in these processes. Interestingly, in embryos with severely reduced Scl levels, erythroid progenitors expressing gata1 and embryonic globin developed. Erythroid maturation was deficient in these Scl hypomorphs, supporting that Scl was required both for the erythroid specification and for the maturation steps, with maturation requiring higher Scl levels than specification. Although all hematopoietic functions were rescued by wild-type Scl mRNA, an Scl DNA binding mutant rescued primitive and definitive hematopoiesis but did not rescue primitive erythroid maturation. Together, we showed that there is a distinct Scl hypomorphic phenotype and demonstrated that distinct functions are required for the roles of Scl in the specification and differentiation of primitive and definitive hematopoietic lineages. Our results revealed that Scl participates in multiple processes requiring different levels and functions. Further, we identified an Scl hypomorphic phenotype distinct from the null state.

Received for publication, July 22, 2005 , and in revised form, October 6, 2005.

^* This work was supported by National Institutes of Health Grant K22-CA095024-02 (to S. E. L.) and a grant from the University of Michigan Medical Scientist Training Program (to M. J. K). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, Division of Hematology-Oncology and Cellular and Molecular Biology Program, University of Michigan, Medical Sciences Bldg. I, Rm. 5315, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0612. Tel.: 734-615-6412; Fax: 734-615-7012; E-mail: suslyons{at}umich.edu.

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