Several gene products expressed in mouse submaxillary gland whose levels appear to be modulated by hormonal effectors are under investigation by molecular and genetic methods with the long-term goal of establishing the mechanism(s) regulating their expression. Work is presently focused on the genes for submaxillary (SMG) and kidney renin. Kidney renin is an aspartyl protease that plays a key role in blood pressure homeostasis. It has recently become clear that the major component of SMG renin is encoded by a separate, closely related gene, tightly linked to the other on the mouse genetic map. These genes, termed Ren-1 and Ren-2, exhibit genetic polymorphisms within inbred mouse strains. In particular, some strains of mice lack the Ren-2 gene copy. Analysis of renin expression in different tissues of the mouse indicates that the Ren-1 and Ren-2 genes differ markedly (up to 100 fold) in their relative levels of expression. Ren-1 is efficiently expressed in kidney but only poorly in submaxillary gland, while Ren-2 is efficiently expressed in submaxillary gland and only poorly, if at all, in kidney. Other tissues have been identified as primary sites of renin synthesis, e.g. adrenal gland and testes although, as yet, the gene specificity of expression in these tissues is unclear. In an effort to understand the basis for these marked differences in tissue and gene specificity of expression, and the modulation of these expressions by hormonal effectors and other agents, detailed analysis of the genomic sequences corresponding to the Ren-1 and Ren-2 genes, and the transcripts originating from these loci is being undertaken. cDNA clones for Ren-2D and Ren-1D have been isolated and characterized and have been used to recover genomic clones, from Lambda and cosmid libraries, that correspond to the Ren-2D, Ren-1D, and Ren-1C loci. These recombinants should provide a suitable starting point for further studies aimed at identifying those sequences, or aspects of structure, responsible for the differential tissue specificity of expression of these genes and their differential responsiveness to hormonal effectors. Surrogate genetic approaches entailing reintroduction of these genes in normal and modified form into cells in culture and the construction of transgenic mice will be used to define these structure-function relationships.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030248-07
Application #
3277897
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1982-02-01
Project End
1990-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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Sigmund, C D; Okuyama, K; Ingelfinger, J et al. (1990) Isolation and characterization of renin-expressing cell lines from transgenic mice containing a renin-promoter viral oncogene fusion construct. J Biol Chem 265:19916-22
Sigmund, C D; Jones, C A; Mullins, J J et al. (1990) Expression of murine renin genes in subcutaneous connective tissue. Proc Natl Acad Sci U S A 87:7993-7
Ratty, A K; Fitzgerald, L W; Titeler, M et al. (1990) Circling behavior exhibited by a transgenic insertional mutant. Brain Res Mol Brain Res 8:355-8

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