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PMID: 2005897 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

An upstream regulatory region mediates high-level, tissue-specific expression of the human alpha 1(I) collagen gene in transgenic mice.

Molecular and cellular biology ·Vol. 11 ·No. 4 ·1991-04-00 ·Pages 2066-74

Slack JL, Liska DJ, Bornstein P

Abstract

Studies in vitro have not adequately resolved the role of intronic and upstream elements in regulating expression of the alpha 1(I) collagen gene. To address this issue, we generated 12 separate lines of transgenic mice with alpha 1(I) collagen-human growth hormone (hGH) constructs containing different amounts of 5'-flanking sequence, with or without most of the first intron. Transgenes driven by 2.3 kb of alpha 1(I) 5'-flanking sequence, whether or not they contained the first intron, were expressed at a high level and in a tissue-specific manner in seven out of seven independent lines of transgenic mice. In most tissues, the transgene was expressed at levels approaching that of the endogenous alpha 1(I) gene and was regulated identically with the endogenous gene as animals aged. However, in lung, expression of the transgene was anomalously high, and in muscle, expression was lower than that of the endogenous gene, suggesting that in these tissues other regions of the gene may participate in directing appropriate expression. Five lines of mice were generated containing transgenes driven by 0.44 kb of alpha 1(I) 5'-flanking sequence (with or without the first intron), and expression was detected in four out of five of these lines. The level of expression of the 0.44-kb constructs in the major collagen-producing tissues was 15- to 500-fold lower than that observed with the longer 2.3-kb promoter. While transgenes containing the 0.44-kb promoter and the first intron retained a modest degree of tissue-specific expression, those without the first intron lacked tissue specificity and were poorly expressed in all tissues except lung. These results contribute to our understanding of the role of the first intron in regulating alpha1(I) gene expression and identify a region, upstream of the basal alpha1(I) promotor, which is necessary for full tissue-specific, developmentally regulated expression of the alpha1(I) collagen gene.

MeSH Terms
Animals Base Sequence Cloning, Molecular Collagen/biosynthesis,genetics Gene Expression Regulation Genes Growth Hormone/pharmacology Humans Introns Lung/metabolism Mice Mice, Transgenic Molecular Sequence Data Organ Specificity/genetics Regulatory Sequences, Nucleic Acid Restriction Mapping
Chemicals
Growth Hormone Collagen
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Slack J L
Department of Biochemistry, University of Washington, Seattle 98195.
Liska D J
Bornstein P
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42 references, click to expand
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/mcb.11.4.2066-2074.1991
Published
1991-04-00
Pages
2066-74
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC359894
Subset
IM
Grants
NIAMS NIH HHS · AR 01846 · United States
NIAMS NIH HHS · AR 08095 · United States
NIAMS NIH HHS · AR 11248 · United States
External Links
PubMed source DOI: 10.1128/mcb.11.4.2066-2074.1991 PMC Full Text View journal details
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