Two-Step Regulation of Ad4BP/SF-1 Gene Transcription during Fetal Adrenal Development: Initiation by a Hox-Pbx1-Prep1 Complex and Maintenance via Autoregulation by Ad4BP/SF-1

Abstract

The orphan nuclear receptor Ad4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor 1) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/SF-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. In this study, we used transgenic mouse assays to examine the regulation of the tissue-specific expression of Ad4BP/SF-1. An investigation of the entire Ad4BP/SF-1 gene locus revealed a fetal adrenal enhancer (FAdE) in intron 4 containing highly conserved binding sites for Pbx-Prep, Pbx-Hox, and Ad4BP/ SF-1. Transgenic assays revealed that the Ad4 sites, together with Ad4BP/SF-1, develop an autoregulatory loop and thereby maintain transcription, while the Pbx/Prep and Pbx/Hox sites initiate transcription prior to the establishment of the autoregulatory loop. Indeed, a limited number of Hox family members were found to be expressed in the adrenal primordia. Whether a true fetal-type adrenal cortex is present in mice remained controversial, and this argument was complicated by the postnatal development of the so-called X zone. Using transgenic mice with lacZ driven by the FAdE, we clearly identified a fetal adrenal cortex in mice, and the X zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth.

Transition from organogenesis to stem cell maintenance in the mouse adrenal cortex

“…14 The greater degree of staining observed in female adrenals is consistent with reports of more prominent female X zone development. 12,36 Emergence of radial stripes in the developing 21OH/LacZ adrenal cortex.…”

“…Elegant transgenic lineage analyses of mouse adrenocortical organogenesis and maintenance have shown (1) that distinct groups of fetal adrenocortical cells with a common origin form the X zone and definitive adult adrenal cortex 14,15 and (2) that progenitor cells labeled at E14.5 can produce clones of cells that span the cortex and produce all the steroidogenic cell types of the adrenal cortex. 22 Our present results bridge these two observations and show that perinatal adrenal cortical growth occurs by edge-biased growth.…”

“…3B and D), consistent with the short-lived nature of the X zone. 14 Some hypotheses of adrenocortical maintenance have proposed that different zones are maintained independently (see Introduction), which could result in discontinuous stripes. To investigate this possibility, stripes were examined in 6-10 serial sections taken from the middle of each of 200 adult adrenal glands.…”

Gene dosage effects and transcriptional regulation of early mammalian adrenal cortex development

“…This indicated that Sf-1 was dispensable for the initiation of expression of its own fetal adrenal enhancer. It was nonetheless required at later stages of development as shown by the absence of expression of the mutated transgene in the E17.5 adrenal [3]. Interestingly, mice lacking Pbx1, a member of the TALE family of homeodomain transcription factors, lacked adrenals at E14.5, had rudimentary gonads (but no sex reversal) and showed renal abnormalities.…”

“…This 600 bp enhancer fragment is contained in the fourth intron of Sf-1 and was shown to drive specific reporter gene expression to the adrenal primordium of transgenic mice, as early as E10.5 [3]. Therefore, this DNA region was called Fetal Adrenal Enhancer or FAdE.…”