Mutation of mouse Cyp11a1 promoter caused tissue-specific reduction of gene expression and blunted stress response without affecting reproduction

Meng Chun Shih, Nai Chi Hsu, Chen Che Huang, Tzong Shoon Wu, Pao Yen Lai, Bon Chu Chung

Research output: Contribution to journalArticle

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Abstract

Steroids are synthesized mainly from the adrenal glands catalyzed by steroidogenic enzymes; the expression of these enzymes is controlled by transcription factor steroidogenic factor-1 (SF-1; NR5A1). To understand the physiological effect of genetic changes on steroid secretion, we used Cre-LoxP and gene targeting technology to mutate the binding sequence for SF-1 (SF-1 response element) on the promoter of the mouse Cyp11a1 gene, which encodes a critical enzyme for steroid biosynthesis. The resulting Cyp11a1L/L mice expressed about 7-fold less cytochrome P450 side-chain cleavage enzyme (CYP11A1) in the adrenal and testis but expressed normal amounts of CYP11A1 in the placenta and ovary. This tissue-specific reduction of gene expression did not affect basal steroid secretion but attenuated the circadian rhythm of glucocorticoid secretion. These mice also failed to induce glucocorticoid secretion in response to stress, leading to retention of CD4+CD8 + double-positive thymocytes. Unlike complete Cyp11a1 disruption, which causes neonatal death, promoter mutation did not decrease life span and caused no defect in reproduction. Thus, CYP11A1 appears in normal mice to be expressed above the minimal required level, providing a large capacity for use in response to stress. Mutation of the SF-1 response element of Cyp11a1 results in reduced stress response due to decreased adrenal CYP11A1 expression and insufficient stress-induced glucocorticoids secretion.

Original languageEnglish
Pages (from-to)915-923
Number of pages9
JournalMolecular Endocrinology
Volume22
Issue number4
DOIs
Publication statusPublished - Apr 1 2008

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Cholesterol Side-Chain Cleavage Enzyme
Reproduction
Steroids
Glucocorticoids
Gene Expression
Mutation
Response Elements
Enzymes
Steroidogenic Factor 1
Gene Targeting
Thymocytes
Adrenal Glands
Circadian Rhythm
Cytochrome P-450 Enzyme System
Placenta
Testis
Cause of Death
Ovary
Transcription Factors
Technology

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

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Mutation of mouse Cyp11a1 promoter caused tissue-specific reduction of gene expression and blunted stress response without affecting reproduction. / Shih, Meng Chun; Hsu, Nai Chi; Huang, Chen Che; Wu, Tzong Shoon; Lai, Pao Yen; Chung, Bon Chu.

In: Molecular Endocrinology, Vol. 22, No. 4, 01.04.2008, p. 915-923.

Research output: Contribution to journalArticle

Shih, Meng Chun ; Hsu, Nai Chi ; Huang, Chen Che ; Wu, Tzong Shoon ; Lai, Pao Yen ; Chung, Bon Chu. / Mutation of mouse Cyp11a1 promoter caused tissue-specific reduction of gene expression and blunted stress response without affecting reproduction. In: Molecular Endocrinology. 2008 ; Vol. 22, No. 4. pp. 915-923.
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