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J. Biol. Chem., Vol. 276, Issue 1, 593-600, January 5, 2001
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From the In human, germ line mutations in the
tumor suppressor retinoblastoma (Rb) predispose individuals to
retinoblastoma, whereas somatic inactivation of Rb contributes to the
progression of a large spectrum of cancers. In mice, Rb is highly
expressed in restricted cell lineages including the neurogenic,
myogenic, and hematopoietic systems, and disruption of the gene leads
to specific embryonic defects in these tissues. The symmetry between Rb
expression and the defects in mutant mice suggest that transcriptional
control of Rb during embryogenesis is pivotal for normal development. We have initiated studies to dissect the mechanisms of transcriptional regulation of Rb during development by promoter lacZ
transgenic analysis. DNA sequences up to 6 kilobase pairs upstream of
the mouse Rb promoter, isolated from two different genomic libraries, directed transgene expression exclusively to the developing nervous system, excluding skeletal muscles and liver. Expression of the transgene in the central and peripheral nervous systems, including the
retina, recapitulated the expression of endogenous Rb during embryogenesis. A promoter region spanning ~250 base pairs upstream of
the transcriptional starting site was sufficient to confer expression
in the central and peripheral nervous systems. To determine whether
this expression pattern was conserved, we isolated the human Rb 5'
genomic region and generated transgenic mice expressing lacZ under control of a 1.6-kilobase pair human Rb
promoter. The human Rb promoter lacZ mice also expressed
the transgene primarily in the nervous system in several independent
lines. Thus, transgene expression directed by both the human and mouse
Rb promoters is restricted to a subset of tissues in which Rb is
normally expressed during embryogenesis. Our findings demonstrate that
regulatory elements directing Rb expression to the nervous system are
delineated within a well defined core promoter and are regionally
separated from elements, yet to be identified, that are required for
expression of Rb in the developing hematopoietic and skeletal muscle systems.
Retinoblastoma Gene Promoter Directs Transgene Expression
Exclusively to the Nervous System*
§,§,,
Departments of Medicine and Medical
Biophysics, University of Toronto and Toronto General Research
Institute, University Health Network, Toronto, Ontario, Canada M5G 2MI;
and the ¶ Developmental Biology Program, Cancer and Blood Program,
Hospital for Sick Children and Department of Medical Genetics,
University of Toronto, Toronto, Ontario, Canada M5G
*
This work was supported by Grant MT-14314 from the Medical
Research Council of Canada (to E. Z.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of a scholarship from the Cancer Research Society
Inc./Medical Research Council of Canada. To whom correspondence should
be addressed: Depts. of Medicine and Medical Biophysics, University of
Toronto, Toronto General Research Institute, University Health Network,
67 College St., Rm. 407, Toronto, Ontario M5G 2M1, Canada. Tel.:
416-340-5106; Fax: 416-340-3453; E-mail:
eldad.zacksenhaus@utoronto.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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