title: Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response.
abstract: Adrenal steroids are essential for homeostasis and survival during severe physiological stress. Analysis of a patient heterozygous for the steroidogenic factor-1 (SF-1) gene suggested that reduced expression of this nuclear receptor leads to adrenal failure. We therefore examined SF-1 heterozygous (+/-) mice as a potential model for delineating mechanisms underlying this disease. Here we show that SF-1 +/- mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein StAR, help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF-1 heterozygotes are revealed under stressful conditions, demonstrating that normal gene dosage of SF-1 is required for mounting an adequate stress response. Our findings predict that natural variations leading to reduced SF-1 function may underlie some forms of subclinical adrenal insufficiency, which become life threatening during traumatic stress.
authors: Department of Physiology, Graduate Programs in Biomedical Sciences and Developmental Biology, University of California, San Francisco, CA 94143, USA.
authors: M L
authors: ML
authors: Bland
authors: C A
authors: CA
authors: Jamieson
authors: S F
authors: SF
authors: Akana
authors: S R
authors: SR
authors: Bornstein
authors: G
authors: G
authors: Eisenhofer
authors: M F
authors: MF
authors: Dallman
authors: H A
authors: HA
authors: Ingraham
mesh_terms: D000311:Adrenal Glands / Q000254:growth & development* / Q000473:pathology; D000313:Adrenal Medulla / Q000473:pathology; D000483:Alleles; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D051717:Fushi Tarazu Transcription Factors; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D044103:Receptor, Melanocortin, Type 2; D018043:Receptors, Corticotropin / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D044103:Receptor, Melanocortin, Type 2; D018043:Receptors, Corticotropin; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse