Transgenic rescue of SF-1-null mice.
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 approximately 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.
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Tatiana
T
Karpova
R R M
RR
Maran
Jeremy
J
Presley
Serge P
SP
Scherrer
Lovella
L
Tejada
Leslie L
LL
Heckert
D000818:Animals; D002454:Cell Differentiation; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D007985:Leydig Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054339:Steroidogenic Factor 1; D013737:Testis / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019076:Transgenes / Q000235:genetics
D018398:Homeodomain Proteins; C417002:NR5A2 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; C515060:steroidogenic factor 1, rat