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Transgenic Rescue of SF‐1‐Null Mice
Author(s) -
KARPOVA TATIANA,
MARAN R. R. M.,
PRESLEY JEREMY,
SCHERRER SERGE P.,
TEJADA LOVELLA,
HECKERT LESLIE L.
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1336.007
Subject(s) - transgene , biology , steroidogenic factor 1 , genetically modified mouse , allele , gene , gene expression , androgen receptor , messenger rna , microbiology and biotechnology , endocrinology , medicine , nuclear receptor , genetics , transcription factor , prostate cancer , cancer
A bstract : Steroidogenic factor 1 (SF‐1, Nr5a1, and Ad4bp) is an orphan nuclear receptor required for adrenal and gonad development and endocrine regulation. To extend our understanding of SF‐1 function and the mechanisms controlling its expression, a transgenic rescue strategy was employed to locate important transcriptional control regions and to reveal functional roles of the protein. A rat yeast artificial chromosome containing Ftz‐F1 , the gene encoding SF‐1, was used to generate mice with different transgenes that varied in size. Rat SF‐1 mRNA expression was assayed to assess each transgene's targeting ability. SF‐1‐deficient/transgene‐positive (SF‐1 −/− ; tg/ + ) “rescue” mice were then generated and the animals' developmental and reproductive status was evaluated. The results identified differences in expression patterns and rescue abilities that provided insight into SF‐1 transcriptional control and function. Comparing transgene maps and mRNA profiles placed critical transcriptional elements for pituitary and hypothalamic expression to a region 3′ to intron 4, whereas examination of rescued mice revealed that an ∼153‐kb region of the Ftz‐F1 locus recapitulates most or all activity ascribed to the endogenous allele. A second line of rescued mice was hypomorphic, with males showing defects in androgen‐dependent tissues due to abnormal Leydig cell differentiation. Histological analysis of embryonic (e14.5) and adult testes from these mice implicated SF‐1 in roles that are distinct in fetal and adult Leydig cells.