ABSTRACT
The formation of the adrenal cortex in humans is notable for the presence of two discrete zones, the fetal zone (FZ) which regresses soon after birth and the definitive zone (DZ) which gives rise to the classic steroidogenic zones of the adult cortex. Mice possess an analogous structure to the FZ referred to as the X-zone (XZ) which regresses at puberty in the male and during the first pregnancy in the female. Similar to the human FZ in X-linked Congenital Adrenal Hypoplasia caused by loss of function mutations in DAX-1 (Dosage-sensitive sex reversal-Adrenal hypoplasia congenita critical region on the X chromosome), the mouse XZ does not regress when DAX-1 is mutated. Only in humans with DAX-1 mutations, however, is the DZ small and hypofunctional. Patients and mice with SF-1 mutations have complete adrenal aplasia with absence of both the DZ and FZ/XZ. Lastly, the phenotype of the Autosomal Recessive Adrenocortical Dysplasia (acd) mouse is strikingly similar to human Miniature Adult Congenital Adrenal Hypoplasia, lacking an XZ/FZ and possessing a dysfunctional DZ. Current work has addressed the regulation of SF-1 and DAX-1 dependent adrenocortical growth and steroidogenesis in vivo utilizing mouse models of simple and combined SF-1 and DAX-1 deficiency. In addition, the model of compensatory adrenal growth in SF-1 haplo-insufficient mice has been applied to evaluate the potential role of SF-1 in adrenocortical proliferation. Additional efforts aim to positionally clone the acd gene, predicated on the hypothesis that it is a critical component of the adrenal developmental cascade.
Subject(s)
Adrenal Cortex Diseases/genetics , DNA-Binding Proteins/genetics , Genes, Recessive , Mutation , Receptors, Retinoic Acid/genetics , Repressor Proteins , Transcription Factors/genetics , Adrenal Cortex/embryology , Adrenal Cortex/growth & development , Adrenal Cortex/metabolism , Animals , DAX-1 Orphan Nuclear Receptor , Embryonic and Fetal Development , Fushi Tarazu Transcription Factors , Homeodomain Proteins , Humans , Mice , Receptors, Cytoplasmic and Nuclear , Steroidogenic Factor 1 , Steroids/biosynthesisABSTRACT
The mechanisms by which SF-1 (Steroidogenic Factor-1) and Dax-1 (Dosage-sensitive sex reversal-Adrenal hypoplasia congenita critical region on the X chromosome) dictate adrenal-specific transcriptional programs are the focus of this laboratory. SF-1-mediated transcription is upregulated by phosphorylation of serine 203 located in the hinge region of SF-1. An SF-1S203A mutant attenuates SF-1 activation, while substitution of S203 with a charged aspartate (SF-1S203D) results in a dose dependent increase in SF-1 mediated transcription. Ser203 serves as a substrate for Erk2 in vitro and is critical for activation of SF-1 by multiple components of the MAPK pathway. Isoelectric focusing demonstrates multiple immuno-reactive SF-1 species in mouse adrenal and NCI-H295A cell extracts. We propose that differential phosphorylation of SF-1 by various mitogens serves to couple extracellular signals to adrenal-specific transcriptional programs. Mouse studies utilizing SF-1 heterozygous mice explore the in vivo role of SF-1 levels, SF-1 phosphorylation and SF-1 interaction with Dax-1 in adrenal steroidogenesis. SF-1 heterozygous mice exhibit a marked decrease in baseline and post-stress corticosterone with a concomitant increase in ACTH. The role of Dax-1 in these SF-1 dependent processes is explored in compound SF-1 (+/-)/Dax-1 KO mice that exhibit an increase in basal corticosterone and a decrease in basal ACTH compared to simple SF-1 (+/-) mice. These finding are consistent with an inhibitory role for Dax-1 in SF-1 mediated transcription. Mice that express epitope tagged SF-1 (wild type, SF-1S203A and SF-1S203D) are being used to rescue the heterozygous adrenal phenotype and to determine the in vivo role of SF-1 phosphorylation in adrenal function.
