Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice
Open accessAbstract
The immediate-early gene NGFI-B encodes an orphan nuclear receptor that binds DNA as a monomer and activates transcription through a canonical response element (NBRE). NGFI-B is expressed under basal conditions and in response to external stimuli in many mammalian tissues. In particular, NGFI-B expression is dramatically elevated in the adrenal cortex in response to stress and in Y1 adrenocortical cells in response to adrenocorticotropin. NGFI-B activates transcription through an NBRE of the gene encoding 21-hydroxylase (P450c21) in Y1 cells. Steroidogenic factor 1 (SF-1), a homolog of NGFI-B, also activates the P450c21 promoter. To examine the influence of these factors on P450c21 expression in vivo and the function of the hypothalamic-pituitary-adrenocortical axis as a whole, we generated NGFI-B (-/-) mice. These mice thrive and reproduce normally and maintain normal basal adrenocorticotropin, corticosterone, and P450c21 mRNA levels. In response to increases in adrenocorticotropin, NGFI-B (-/-) and wild-type mice demonstrated equivalent increases in serum corticosterone levels. Furthermore, and in contrast to in vitro results, no increases in P450c21 mRNA levels were observed in response to increases in adrenocorticotropin in NGFI-B (-/-) or wild-type mice. While SF-1 mRNA levels were not increased with increased steroidogenic demand, adrenal expression of Nurr1, a close homolog of NGFI-B, was induced to a greater extent by lipopolysaccharide in NGFI-B (-/-) mice than in wild-type mice. Finally, when the administration of dexamethasone for suppression was stopped, P450c21 mRNA and serum corticosterone levels recovered at the same rate in wild-type and NGFI-B (-/-) mice. Thus, while NGFI-B appears poised to affect the structure and function of the adrenal gland, the gland functions normally in its absence, suggesting that other factors, including Nurr1 and SF-1, are sufficient to drive P450c21 expression in mice and maintain normal steroidogenesis.
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Steroidogenic factor-1 interacts with specific DNA elements both within the proximal promoter and in intron 35 of the linked C4B gene.
“It interacts with specific DNA elements both within the proximal promoter and in intron 35 of the linked C4B gene (183).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [183]
Without exhaustive sequencing, it is difficult to rule out the existence of additional mutations in introns or flanking regions that might affect mRNA processing or gene expression.
“Without exhaustive sequencing, it is difficult to rule out the existence of additional mutations in introns or flanking regions that might affect mRNA processing or gene expression; as noted in section III.B.3, one transcriptional control region is several kilobases away from CYP21A2, in the C4B gene (183).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [183]
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References 38 · Cited by 145
- Authors
- Crawford, P. A., Sadovsky, Y., Woodson, K., Lee, S. L., & Milbrandt, J.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1995-08-01
- Volume
- 15
- Issue
- 8
- Pages
- 4331-4336
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC230672
- OpenAlex
- W2119446658
- Cited by
- 145
- References
- 38
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 4
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5p01ca049712-10)
- National Cancer Institute (P01-CA49712)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- Nur77, 21-hydroxylase, P450c21, steroidogenesis, adrenocortical function, steroidogenic factor 1, Nurr1, ACTH, corticosterone, hypothalamic-pituitary-adrenal axis, transcriptional regulation, lipopolysaccharide, dexamethasone suppression, knockout mice
- MeSH terms
- Adrenal Cortex, Adrenocorticotropic Hormone, Animals, Corticosterone, Dexamethasone, DNA-Binding Proteins, Hypothalamo-Hypophyseal System, Lipopolysaccharides, Metyrapone, Mice, Mutant Strains, Pituitary-Adrenal System, Receptors, Steroid, RNA, Messenger, Steroid 21-Hydroxylase, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Enzymologic, Receptors, Cytoplasmic and Nuclear, Homeodomain Proteins, Mice, Fushi Tarazu Transcription Factors, Steroidogenic Factor 1, Nuclear Receptor Subfamily 4, Group A, Member 1
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