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Blood, 1 June 2002, Vol. 99, No. 11, pp. 3931-3938
HEMATOPOIESIS
Rescue of the lethal scl / phenotype by
the human SCL locus
Angus M. Sinclair,
Anthony
J. Bench,
Adrian J. C. Bloor,
Juan Li,
Berthold Göttgens,
Maureen L. Stanley,
Jane Miller,
Sandie Piltz,
Susie Hunter,
Elisabeth P. Nacheva,
María-José Sanchez, and
Anthony R. Green
From the University of Cambridge, Department of
Haematology, Cambridge Institute for Medical Research, Hills Road,
Cambridge, CB2 2XY, United Kingdom.
The stem cell leukemia (SCL) gene encodes a
basic helix-loop-helix transcription factor with a critical role in the
development of both blood and endothelium. Loss-of-function studies
have shown that SCL is essential for the formation of hematopoietic
stem cells, for subsequent erythroid development and for yolk sac
angiogenesis. SCL exhibits a highly conserved pattern of
expression from mammals to teleost fish. Several murine SCL
enhancers have been identified, each of which directs reporter gene
expression in vivo to a subdomain of the normal SCL expression pattern.
However, regulatory elements necessary for SCL expression in erythroid
cells remain to be identified and the size of the chromosomal domain
needed to support appropriate SCL transcription is unknown.
Here we demonstrate that a 130-kilobase (kb) yeast artificial
chromosome (YAC) containing the human SCL locus
completely rescued the embryonic lethal phenotype of
scl / mice. Rescued YAC+
scl/ mice were born in appropriate
Mendelian ratios, were healthy and fertile, and exhibited no detectable
abnormality of yolk sac, fetal liver, or adult hematopoiesis. The human
SCL protein can therefore substitute for its murine homologue. In
addition, our results demonstrate that the human SCL YAC
contains the chromosomal domain necessary to direct expression to the
erythroid lineage and to all other tissues in which SCL performs a
nonredundant essential function.
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