Differential requirement for steroidogenic factor-1 gene dosage in adrenal development versus endocrine function.
The importance of steroidogenic factor-1 (SF-1) gene dosage in endocrine function is evidenced by phenotypes associated with the heterozygous state in mice and humans. Here we examined mechanisms underlying SF-1 haploinsufficiency and found a striking reduction (12-fold) in SF-1 heterozygous (+/-) adrenocortical size at embryonic day (E) 12. Loss of one SF-1 allele led to a selective decrease in adrenal precursors within the adrenogonadal primordium at E10.0, without affecting the number of gonadal precursors, as marked by GATA-4. Beginning at E13.5, increased cell proliferation in SF-1 +/- adrenals allows these organs to approach but not attain a normal size. Remarkably, neural crest-derived adrenomedullary precursors migrated normally in SF-1 +/- and null embryos. However, later in development, medullary growth was compromised in both genotypes. Despite the small adrenal size in SF-1heterozygotes, an unexpected elevation in steroidogenic capacity per cell was observed in primary adult adrenocortical SF-1 +/- cells compared with wild-type cells. Elevated cellular steroid output is consistent with the up-regulation of some SF-1 target genes in SF-1 +/- adrenals and may partially be due to an observed increase in nerve growth factor-induced-B. Our findings underscore the need for full SF-1 gene dosage early in adrenal development, but not in the adult adrenal, where compensatory mechanisms restore near normal function.
Bland
Michelle L
ML
Department of Physiology, Biomedical Sciences Graduate Program, University of California-San Francisco, Box 0444, San Francisco, CA 94143-0444, USA.
Fowkes
Robert C
RC
Ingraham
Holly A
HA
D000311:Adrenal Glands / Q000196:embryology* / Q000502:physiology*; D000818:Animals; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051717:Fushi Tarazu Transcription Factors; D018628:Gene Dosage; D006579:Heterozygote; D051379:Mice; D000072260:RNA Splicing Factors; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D000072260:RNA Splicing Factors; C491514:Sf1 protein, mouse; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse