Article

Distinct roles for SCL in erythroid specification and maturation in zebrafish.

Department of Internal Medicine, Division of Hematology-Oncology and Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
Journal of Biological Chemistry (impact factor: 4.77). 01/2006; 280(50):41636-44. DOI:10.1074/jbc.M507998200 pp.41636-44
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: The stem-cell leukemia (SCL, also known as TAL1) gene encodes a basic helix-loop-helix transcription factor that is essential for the initiation of primitive and definitive hematopoiesis, erythrocyte and megakarocyte differentiation, angiogenesis, and astrocyte development. Here we report that the zebrafish produces, through an alternative promoter site, a novel truncated scl (tal1) isoform, scl-beta, which manifests a temporal and spatial expression distinct from the previously described full-length scl-alpha. Functional analysis reveals that while scl-alpha and -beta are redundant for the initiation of primitive hematopoiesis, these two isoforms exert distinct functions in the regulation of primitive erythroid differentiation and definitive hematopoietic stem cell specification. We further demonstrate that differences in the protein expression levels of scl-alpha and -beta, by regulating their protein stability, are likely to give rise to their distinct functions. Our findings suggest that hematopoietic cells at different levels of hierarchy are likely governed by a gradient of the Scl protein established through temporal and spatial patterns of expression of the different isoforms.
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Keywords

ablating Scl
 
definitive hematopoiesis
 
definitive hematopoietic lineages
 
distinct functions
 
distinct Scl hypomorphic phenotype
 
embryonic globin
 
Erythroid maturation
 
erythroid progenitors
 
erythroid specification
 
essential role
 
hematopoietic functions
 
higher Scl levels
 
maturation steps
 
null state
 
powerful zebrafish model
 
rescue primitive erythroid maturation
 
Scl DNA binding mutant
 
Scl participates
 
vertebrate hematopoiesis
 
wild-type Scl mRNA