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A Hyperandrogenic Mouse Model to Study Polycystic Ovary Syndrome
Published on: October 2, 2018
SF1 polymorphisms in the mouse and steroidogenic potential
Bernard P Schimmer1, Martha Cordova, Jennivine Tsao
1Banting and Best Department of Medical Research, University of Toronto, Toronto, ON Canada M5G 1L6. bernard.schimmer@utoronto.ca
Abstract:
ACTH-resistance in four mutant derivatives of a mouse adrenocortical tumor cell line results from a defect that reduces the activity of steroidogenic factor-1 (SF1) thereby preventing expression of the ACTH receptor and other SF1-dependent genes. The SF1 genes from these mutants contain a sequence difference that changes an Ala to Ser at codon 172. Steroidogenic factor-1(S172) represents a polymorphism rather than a spontaneous mutation since the two forms of SF1, SF1(A172), and SF1(S172), can be traced to the hybrid mouse strain (C57L/J x A/HeJ) from which the original adrenal tumor was derived. The SF1(S172) allele is amplified in three of the four mutant clones together with the neighboring genes germ cell nuclear factor and LIM homeobox2. The two forms of SF1 had only modest differences in transcriptional activity in reporter gene assays, suggesting that the SF1 polymorphism per se is not directly responsible for the loss of mc2r expression. Rather, ACTH resistance in this family of adrenocortical tumor cell mutants may be due to a closely linked gene on the SF1(S172) allele. Mouse strains with reportedly high steroidogenic capacity (C57Bl/6J, C57Bl/10J) also have the SF1(A172) allele while mouse strains with low steroidogenic capacity (C3H/HeJ, DBA/2J) have the SF1(S172) allele. These latter observations suggest that the two SF1 alleles also may be markers of steroidogenic potential among mouse strains.
Insights
ACTH resistance in mouse adrenal tumors stems from reduced steroidogenic factor-1 (SF1) activity. A specific SF1 polymorphism (S172) may indicate lower steroidogenic potential, possibly due to linked genes.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Adrenocorticotropic hormone (ACTH) resistance in mouse adrenocortical tumor cells is linked to defects in steroidogenic factor-1 (SF1).
- SF1 regulates the expression of key genes in steroidogenesis, including the ACTH receptor (MC2R).
- Mutant cell lines exhibit reduced SF1 activity, impacting MC2R expression and leading to ACTH resistance.
Purpose of the Study:
- To investigate the molecular basis of ACTH resistance in mouse adrenocortical tumor cell mutants.
- To characterize the role of a specific SF1 polymorphism (A172 vs. S172) in steroidogenesis.
- To explore the potential association between SF1 alleles and steroidogenic capacity in different mouse strains.
Main Methods:
- Analysis of SF1 gene sequences in mutant and wild-type cell lines.
- Reporter gene assays to assess the transcriptional activity of different SF1 variants.
- Gene copy number analysis of SF1 and neighboring genes (GCNF, LHX2) in mutant clones.
- Correlation analysis of SF1 alleles with steroidogenic capacity in various mouse strains.
Main Results:
- Mutant cell lines possess an SF1 gene with an Alanine to Serine change at codon 172 (SF1(S172)).
- This SF1(S172) variant is a polymorphism present in the original hybrid mouse strain, not a spontaneous mutation.
- Reporter assays showed only modest differences in transcriptional activity between SF1(A172) and SF1(S172).
- The SF1(S172) allele was amplified in three of four mutants, along with GCNF and LHX2.
- Mouse strains with high steroidogenic capacity possess the SF1(A172) allele, while those with low capacity have the SF1(S172) allele.
Conclusions:
- ACTH resistance in these mutants is likely caused by a gene linked to the SF1(S172) allele, rather than the polymorphism itself.
- The SF1(S172) allele may serve as a marker for reduced steroidogenic potential in mice.
- Further research is needed to identify the specific linked gene responsible for the observed ACTH resistance.
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